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1
Clough, Barbara, Ryan Finethy, Rabia T. Khan, et al. "C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo." Wellcome Open Research 4 (August 20, 2019): 124. http://dx.doi.org/10.12688/wellcomeopenres.15329.1.
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Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.
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Feeley, Eric M., Danielle M. Pilla-Moffett, Erin E. Zwack, et al. "Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems." Proceedings of the National Academy of Sciences 114, no. 9 (2017): E1698—E1706. http://dx.doi.org/10.1073/pnas.1615771114.
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Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as “patterns of pathogenesis” associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersinia-containing vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3–deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3–dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.
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Legewie, Larissa, Jennifer Loschwitz, Nora Steffens, et al. "Biochemical and structural characterization of murine GBP7, a guanylate binding protein with an elongated C-terminal tail." Biochemical Journal 476, no. 21 (2019): 3161–82. http://dx.doi.org/10.1042/bcj20190364.
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Abstract Guanylate-binding proteins (GBPs) constitute a family of interferon-inducible guanosine triphosphatases (GTPases) that are key players in host defense against intracellular pathogens ranging from protozoa to bacteria and viruses. So far, human GBP1 and GBP5 as well as murine GBP2 (mGBP2) have been biochemically characterized in detail. Here, with murine GBP7 (mGBP7), a GBP family member with an unconventional and elongated C-terminus is analyzed. The present study demonstrates that mGBP7 exhibits a concentration-dependent GTPase activity and an apparent GTP turnover number of 20 min−1. In addition, fluorescence spectroscopy analyses reveal that mGBP7 binds GTP with high affinity (KD = 0.22 µM) and GTPase activity assays indicate that mGBP7 hydrolyzes GTP to GDP and GMP. The mGBP7 GTPase activity is inhibited by incubation with γ-phosphate analogs and a K51A mutation interfering with GTP binding. SEC-MALS analyses give evidence that mGBP7 forms transient dimers and that this oligomerization pattern is not influenced by the presence of nucleotides. Moreover, a structural model for mGBP7 is provided by homology modeling, which shows that the GTPase possesses an elongated C-terminal (CT) tail compared with the CaaX motif-containing mGBP2 and human GBP1. Molecular dynamics simulations indicate that this tail has transmembrane characteristics and, interestingly, confocal microscopy analyses reveal that the CT tail is required for recruitment of mGBP7 to the parasitophorous vacuole of Toxoplasma gondii.
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Srinivasachar Badarinarayan, Smitha, Irina Shcherbakova, Simon Langer, et al. "HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression." Nucleic Acids Research 48, no. 19 (2020): 10890–908. http://dx.doi.org/10.1093/nar/gkaa832.
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Abstract Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.
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Yu, Peifa, Yang Li, Yunlong Li, Zhijiang Miao, Maikel P. Peppelenbosch, and Qiuwei Pan. "Guanylate-binding protein 2 orchestrates innate immune responses against murine norovirus and is antagonized by the viral protein NS7." Journal of Biological Chemistry 295, no. 23 (2020): 8036–47. http://dx.doi.org/10.1074/jbc.ra120.013544.
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Noroviruses are the main causative agents of acute viral gastroenteritis, but the host factors that restrict their replication remain poorly identified. Guanylate-binding proteins (GBPs) are interferon (IFN)-inducible GTPases that exert broad antiviral activity and are important mediators of host defenses against viral infections. Here, we show that both IFN-γ stimulation and murine norovirus (MNV) infection induce GBP2 expression in murine macrophages. Results from loss- and gain-of-function assays indicated that GBP2 is important for IFN-γ–dependent anti-MNV activity in murine macrophages. Ectopic expression of MNV receptor (CD300lf) in human HEK293T epithelial cells conferred susceptibility to MNV infection. Importantly, GBP2 potently inhibited MNV in these human epithelial cells. Results from mechanistic dissection experiments revealed that the N-terminal G domain of GBP2 mediates these anti-MNV effects. R48A and K51A substitutions in GBP2, associated with loss of GBP2 GTPase activity, attenuated the anti-MNV effects of GBP2. Finally, we found that nonstructural protein 7 (NS7) of MNV co-localizes with GBP2 and antagonizes the anti-MNV activity of GBP2. These findings reveal that GBP2 is an important mediator of host defenses against murine norovirus.
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Liu, Bo, Rongfei Huang, Tingting Fu, et al. "GBP2 as a potential prognostic biomarker in pancreatic adenocarcinoma." PeerJ 9 (May 11, 2021): e11423. http://dx.doi.org/10.7717/peerj.11423.
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Background Pancreatic adenocarcinoma (PAAD) is a disease with atypical symptoms, an unfavorable response to therapy, and a poor outcome. Abnormal guanylate-binding proteins (GBPs) play an important role in the host’s defense against viral infection and may be related to carcinogenesis. In this study, we sought to determine the relationship between GBP2 expression and phenotype in patients with PAAD and explored the possible underlying biological mechanism. Method We analyzed the expression of GBP2 in PAAD tissues using a multiple gene expression database and a cohort of 42 PAAD patients. We evaluated GBP2’s prognostic value using Kaplan–Meier analysis and the Cox regression model. GO and KEGG enrichment analysis, co-expression analysis, and GSEA were performed to illustrate the possible underlying biological mechanism. CIBERSORT and the relative expression of immune checkpoints were used to estimate the relationship between GBP2 expression and tumor immunology. Result GBP2 was remarkably overexpressed in PAAD tissue. The overexpression of GBP2 was correlated with an advanced T stage and poor overall survival (OS) and GBP2 expression was an independent risk factor for OS in PAAD patients. Functional analysis demonstrated that positively co-expressed genes of GBP2 were closely associated with pathways in cancer and the NOD-like receptor signaling pathway. Most of the characteristic immune checkpoints, including PDCD1, PDCDL1, CTLA4, CD80, TIGIT, LAG3, IDO2, and VISTA, were significantly expressed in the high-GBP2 expression group compared with the low-GBP2 expression group. Conclusion GBP2 acted as a potential prognostic biomarker and was associated with immune infiltration and the expression of immune checkpoints in PAAD.
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Fry, Lucy, Noah Kelner, and Tiffany Weinkopff. "Host guanylate binding proteins participate in parasite control during Leishmania infection." Journal of Immunology 212, no. 1_Supplement (2024): 0466_5420. http://dx.doi.org/10.4049/jimmunol.212.supp.0466.5420.
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Abstract Cutaneous leishmaniasis (CL) is a debilitating neglected tropical disease causing lesions ranging from self-healing to permanent disfigurations. A predominant Th1 response relying on IFNγ production leads to parasite control during CL. Although IFNγ is mainly responsible for activating macrophages to produce NO leading to parasite control, IFNγ can activate other downstream pathways involved in cell autonomous immunity including the activation of guanylate binding proteins (GBPs), a class of interferon-inducible GTPases. GBPs play a role in host defense against some intracellular pathogens, but minimal work has been done to understand the role of GBPs during Leishmania infection. Utilizing RNA-Seq we found several GBPs are upregulated in lesions during L. major infection in mice. Single-cell RNA-Sequencing revealed macrophages as the main cell type expressing Gbps, including Gbp2, Gbp5, and Gbp7 during infection. Additionally, Gbp expression was not unique to L. major infection; both L. amazonensis and L. mexicana infection in vivo resulted in elevated Gbp expression. Preliminary in vitro experiments show macrophages from GBPChr3 KO mice harbor increased numbers of parasites compared to control macrophages with and without IFNγ treatment. Consistent with in vitro findings, infected GBPChr3 KO mice exhibit increased pathology compared to control mice. Together these data suggest GBPs participate in the defense against Leishmania parasites.
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Gao, Zhenzhen, Zejing Meng, Xiaobing He, et al. "Guanylate-Binding Protein 2 Exerts GTPase-Dependent Anti-Ectromelia Virus Effect." Microorganisms 11, no. 9 (2023): 2258. http://dx.doi.org/10.3390/microorganisms11092258.
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Guanylate-binding proteins (GBPs) are highly expressed interferon-stimulated genes (ISGs) that play significant roles in protecting against invading pathogens. Although their functions in response to RNA viruses have been extensively investigated, there is limited information available regarding their role in DNA viruses, particularly poxviruses. Ectromelia virus (ECTV), a member of the orthopoxvirus genus, is a large double-stranded DNA virus closely related to the monkeypox virus and variola virus. It has been intensively studied as a highly effective model virus. According to the study, GBP2 overexpression suppresses ECTV replication in a dose-dependent manner, while GBP2 knockdown promotes ECTV infection. Additionally, it was discovered that GBP2 primarily functions through its N-terminal GTPase activity, and the inhibitory effect of GBP2 was disrupted in the GTP-binding-impaired mutant GBP2K51A. This study is the first to demonstrate the inhibitory effect of GBP2 on ECTV, and it offers insights into innovative antiviral strategies.
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Ohshima, Jun, Miwa Sasai, Jianfa Liu та ін. "RabGDIα is a negative regulator of interferon-γ–inducible GTPase-dependent cell-autonomous immunity to Toxoplasma gondii". Proceedings of the National Academy of Sciences 112, № 33 (2015): E4581—E4590. http://dx.doi.org/10.1073/pnas.1510031112.
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IFN-γ orchestrates cell-autonomous host defense against various intracellular vacuolar pathogens. IFN-γ–inducible GTPases, such as p47 immunity-related GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), are recruited to pathogen-containing vacuoles, which is important for disruption of the vacuoles, culminating in the cell-autonomous clearance. Although the positive regulation for the proper recruitment of IRGs and GBPs to the vacuoles has been elucidated, the suppressive mechanism is unclear. Here, we show that Rab GDP dissociation inhibitor α (RabGDIα), originally identified as a Rab small GTPase inhibitor, is a negative regulator of IFN-γ–inducible GTPases in cell-autonomous immunity to the intracellular pathogen Toxoplasma gondii. Overexpression of RabGDIα, but not of RabGDIβ, impaired IFN-γ–dependent reduction of T. gondii numbers. Conversely, RabGDIα deletion in macrophages and fibroblasts enhanced the IFN-γ–induced clearance of T. gondii. Furthermore, upon a high dose of infection by T. gondii, RabGDIα-deficient mice exhibited a decreased parasite burden in the brain and increased resistance in the chronic phase than did control mice. Among members of IRGs and GBPs important for the parasite clearance, Irga6 and Gbp2 alone were more frequently recruited to T. gondii-forming parasitophorous vacuoles in RabGDIα-deficient cells. Notably, Gbp2 positively controlled Irga6 recruitment that was inhibited by direct and specific interactions of RabGDIα with Gbp2 through the lipid-binding pocket. Taken together, our results suggest that RabGDIα inhibits host defense against T. gondii by negatively regulating the Gbp2–Irga6 axis of IFN-γ–dependent cell-autonomous immunity.
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Gao, Zhenzhen, Xiaobing He, Guohua Chen, et al. "The Viral Protein Poly(A) Polymerase Catalytic Subunit Interacts with Guanylate-Binding Proteins 2 to Antagonize the Antiviral Ability of Targeting Ectromelia Virus." International Journal of Molecular Sciences 24, no. 21 (2023): 15750. http://dx.doi.org/10.3390/ijms242115750.
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The recent spread of the monkeypox virus among humans has heightened concerns regarding orthopoxvirus infections. Consequently, conducting a comprehensive study on the immunobiology of the monkeypox virus is imperative for the development of effective therapeutics. Ectromelia virus (ECTV) closely resembles the genetic and disease characteristics of monkeypox virus, making it a valuable research tool for studying orthopoxvirus–host interactions. Guanylate-binding proteins (GBPs), highly expressed interferon-stimulated genes (ISGs), have antagonistic effects against various intracellular pathogenic microorganisms. Our previous research has shown that GBP2 has a mild but statistically significant inhibitory effect on ECTV infection. The presence of a significant number of molecules in the poxvirus genome that encode the host immune response raises questions about whether it also includes proteins that counteract the antiviral activity of GBP2. Using IP/MS and co-IP technology, we discovered that the poly(A) polymerase catalytic subunit (PAPL) protein of ECTV is a viral regulatory molecule that interacts with GBP2. Further studies have shown that PAPL antagonizes the antiviral activity of GBP2 by reducing its protein levels. Knocking out the PAPL gene of ECTV with the CRISPR/Cas9 system significantly diminishes the replication ability of the virus, indicating the indispensable role of PAPL in the replication process of ECTV. In conclusion, our study presents preliminary evidence supporting the significance of PAPL as a virulence factor that can interact with GBP2.
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You, Ji-Eun, Eun-Ji Kim, Ho Won Kim, Jong-Seok Kim, Kyunggon Kim, and Pyung-Hwan Kim. "Exploring the Role of Guanylate-Binding Protein-2 in Activated Microglia-Mediated Neuroinflammation and Neuronal Damage." Biomedicines 12, no. 5 (2024): 1130. http://dx.doi.org/10.3390/biomedicines12051130.
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Neuron damage by microglia, which act as macrophage cells in the brain, can result in various brain diseases. However, the function of pro-inflammatory or anti-inflammatory microglia in the neurons remains controversial. Guanylate-binding protein-2 (GBP2) is expressed and activated in the microglia in the early phase of the inflammatory response and plays an important role in controlling immune responses. In this study, we evaluated whether GBP2 initially reduces the immune response induced by microglia, and whether microglia induce pro-inflammatory functions in neurons via GBP2 expression. In lipopolysaccharide (LPS)-stimulated microglia, we assessed the expression of GBP2 and how it affects neurons via activated microglia. The biological functions of microglia due to the downregulation of the GBP2 gene were examined using short hairpin RNA (shRNA)-RNA-GBP2. Downregulated GBP2 affected the function of mitochondria in the microglia and showed reduced neuronal damage when compared to the control group in the co-culture system. Furthermore, this protein was observed to be highly expressed in the brains of dementia mice. Our results are the first to report that the downregulation of GBP2 in activated microglia has an anti-inflammatory function. This study suggests that the GBP2 gene can be used as a therapeutic target biomarker for inflammation-related neurodegenerative diseases.
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Zhang, Juan, Yu Zhang, Wenshuang Wu, et al. "Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion." Cell Death & Disease 8, no. 10 (2017): e3151-e3151. http://dx.doi.org/10.1038/cddis.2017.559.
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Abstract Guanylate-binding protein 2 (GBP2) is a member of the large GTPase superfamily that is strongly induced by interferon-γ (IFN-γ). Although the biochemical characteristics of GBP2 have been reported in detail, its biological function has not been thoroughly elucidated to date. To the best of our knowledge, this study presents the first demonstration that GBP2 inhibits mitochondrial fission and cell metastasis in breast cancer cells both in vitro and in vivo. Our previous work demonstrated that dynamin-related protein 1 (Drp1)-dependent mitochondrial fission has a key role in breast cancer cell invasion. In this study, we demonstrate that GBP2 binds directly to Drp1. Elimination of Drp1 by shRNA or Mdivi-1 (a Drp1-specific inhibitor) suppressed GBP2’s regulatory function. Furthermore, GBP2 blocks Drp1 translocation from the cytosol to mitochondria, thereby attenuating Drp1-dependent mitochondrial fission and breast cancer cell invasion. In summary, our data provide new insights into the function and molecular mechanisms underlying GBP2’s regulation of breast cancer cell invasion.
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Wang, Haizhou, Yabo Zhou, Yangyang Zhang, et al. "Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target." Journal for ImmunoTherapy of Cancer 10, no. 4 (2022): e004302. http://dx.doi.org/10.1136/jitc-2021-004302.
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BackgroundsProficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported.MethodsUnsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments.ResultsWe classified 1424 pMMR/MSS CRC patients into two classes, ‘immune’ and ‘non-immune’, and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cells on IFN-γ stimulation. A Transwell assay revealed that deletion of GBP2 in murine MSS CRC cells reduced CD8 +T cell migration. Mechanistically, GBP2 promoted signal transducer and transcription activator 1 (STAT1) phosphorylation by competing with SHP1 for binding to STAT1 in MSS CRC cells. Finally, an unsupervised subclass mapping (SubMap) algorithm showed that pMMR/MSS patients with high GBP2 expression may correlate with a favorable response to anti-PD-1 therapy. We further confirmed that GBP2 knockout reduced CD8 +T cell infiltration and blunted the efficacy of PD-1 blockade in tumor-bearing mice.ConclusionsOur study reveals that pMMR/MSS CRC is immunogenically heterogeneous and that GBP2 is a promising target for combinatorial therapy with ICB.
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Ma, Guojian, Jing Huang, Nunu Sun, et al. "Molecular characterization of the porcine GBP1 and GBP2 genes." Molecular Immunology 45, no. 10 (2008): 2797–807. http://dx.doi.org/10.1016/j.molimm.2008.02.007.
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Kubo, Yoshinao, Manya Bakatumana Hans, Taisuke Nakamura, and Hideki Hayashi. "The Furin Protease Dependence and Antiviral GBP2 Sensitivity of Murine Leukemia Virus Infection Are Determined by the Amino Acid Sequence at the Envelope Glycoprotein Cleavage Site." International Journal of Molecular Sciences 25, no. 18 (2024): 9987. http://dx.doi.org/10.3390/ijms25189987.
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Host restriction factor GBP2 suppresses the replication of the ecotropic Moloney murine leukemia virus (E-MLV) by inhibiting furin protease, which cleaves the viral envelope glycoprotein (Env) into surface (SU) and transmembrane (TM) subunits. We analyzed the impacts of GBP2 on the infection efficiency mediated by MLV Envs of different strains of ecotropic Moloney, polytropic Friend, amphotropic, and xenotropic MLV-related (XMRV) viruses. Interestingly, the Envs of ecotropic Moloney and polytropic Friend MLV were sensitive to the antiviral activity of GBP2, while XMRV and amphotropic Envs showed resistance. Consistent with the sensitivity to GBP2, the amino acid sequences of the sensitive Envs at the SU-TM cleavage site were similar, as were the sequences of the resistant Envs. SU-TM cleavage of the GBP2-sensitive Env protein was inhibited by furin silencing, whereas that of GBP2-resistant Env was not. The substitution of the ecotropic Moloney cleavage site sequence with that of XMRV conferred resistance to both GBP2 and furin silencing. Reciprocally, the substitution of the XMRV cleavage site sequence with that of the ecotropic sequence conferred sensitivity to GBP2 and furin silencing. According to the SU-TM cleavage site sequence, there were sensitive and resistant variants among ecotropic, polytropic, and xenotropic MLVs. This study found that the dependence of MLV Env proteins on furin cleavage and GBP2-mediated restriction is determined by the amino acid sequences at the SU-TM cleavage site.
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Pinheiro, Ana, J. Ricardo Borges, João Vasco Côrte-Real, and Pedro J. Esteves. "Evolution of guanylate binding protein genes shows a remarkable variability within bats (Chiroptera)." Frontiers in Immunology 15 (June 12, 2024): 1329098. https://doi.org/10.5281/zenodo.13435572.
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(Uploaded by Plazi for the Bat Literature Project) Background: GBPs (guanylate binding proteins), an evolutionary ancient protein family, play a key role in the host's innate immune response against bacterial, parasitic and viral infections. In Humans, seven GBP genes have been described (GBP1-7). Despite the interest these proteins have received over the last years, evolutionary studies have only been performed in primates, Tupaia and rodents. These have shown a pattern of gene gain and loss in each family, indicative of the birth-and-death evolution process. Results: In this study, we analysed the evolution of this gene cluster in several bat species, belonging to the Yangochiroptera and Yinpterochiroptera sub-orders. Detailed analysis shows a conserved synteny and a gene expansion and loss history. Phylogenetic analysis showed that bats have GBPs 1,2 and 4-6. GBP2 has been lost in several bat families, being present only in Hipposideidae and Pteropodidae. GBPs1, 4 and 5 are present mostly as single-copy genes in all families but have suffered duplication events, particularly in Myotis myotis and Eptesicus fuscus. Most interestingly, we demonstrate that GBP6 duplicated in a Chiroptera ancestor species originating two genes, which we named GBP6a and GBP6b, with different subsequent evolutionary histories. GBP6a underwent several duplication events in all families while GBP6b is present as a single copy gene and has been lost in Pteropodidae, Miniopteridae and Desmodus rotundus, a Phyllostomidae. With 14 and 15 GBP genes, Myotis myotis and Eptesicus fuscus stand out as having far more copies than all other studied bat species. Antagonistically, Pteropodidae have the lowest number of GBP genes in bats. Conclusion: Bats are important reservoirs of viruses, many of which have become zoonotic diseases in the last decades. Further functional studies on bats GBPs will help elucidate their function, evolutionary history, and the role of bats as virus reservoirs.
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Pinheiro, Ana, J. Ricardo Borges, João Vasco Côrte-Real, and Pedro J. Esteves. "Evolution of guanylate binding protein genes shows a remarkable variability within bats (Chiroptera)." Frontiers in Immunology 15 (June 7, 2024): 1329098. https://doi.org/10.5281/zenodo.13435572.
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(Uploaded by Plazi for the Bat Literature Project) Background: GBPs (guanylate binding proteins), an evolutionary ancient protein family, play a key role in the host's innate immune response against bacterial, parasitic and viral infections. In Humans, seven GBP genes have been described (GBP1-7). Despite the interest these proteins have received over the last years, evolutionary studies have only been performed in primates, Tupaia and rodents. These have shown a pattern of gene gain and loss in each family, indicative of the birth-and-death evolution process. Results: In this study, we analysed the evolution of this gene cluster in several bat species, belonging to the Yangochiroptera and Yinpterochiroptera sub-orders. Detailed analysis shows a conserved synteny and a gene expansion and loss history. Phylogenetic analysis showed that bats have GBPs 1,2 and 4-6. GBP2 has been lost in several bat families, being present only in Hipposideidae and Pteropodidae. GBPs1, 4 and 5 are present mostly as single-copy genes in all families but have suffered duplication events, particularly in Myotis myotis and Eptesicus fuscus. Most interestingly, we demonstrate that GBP6 duplicated in a Chiroptera ancestor species originating two genes, which we named GBP6a and GBP6b, with different subsequent evolutionary histories. GBP6a underwent several duplication events in all families while GBP6b is present as a single copy gene and has been lost in Pteropodidae, Miniopteridae and Desmodus rotundus, a Phyllostomidae. With 14 and 15 GBP genes, Myotis myotis and Eptesicus fuscus stand out as having far more copies than all other studied bat species. Antagonistically, Pteropodidae have the lowest number of GBP genes in bats. Conclusion: Bats are important reservoirs of viruses, many of which have become zoonotic diseases in the last decades. Further functional studies on bats GBPs will help elucidate their function, evolutionary history, and the role of bats as virus reservoirs.
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Pinheiro, Ana, J. Ricardo Borges, João Vasco Côrte-Real, and Pedro J. Esteves. "Evolution of guanylate binding protein genes shows a remarkable variability within bats (Chiroptera)." Frontiers in Immunology 15 (July 3, 2024): 1329098. https://doi.org/10.5281/zenodo.13435572.
Full textAbstract:
(Uploaded by Plazi for the Bat Literature Project) Background: GBPs (guanylate binding proteins), an evolutionary ancient protein family, play a key role in the host's innate immune response against bacterial, parasitic and viral infections. In Humans, seven GBP genes have been described (GBP1-7). Despite the interest these proteins have received over the last years, evolutionary studies have only been performed in primates, Tupaia and rodents. These have shown a pattern of gene gain and loss in each family, indicative of the birth-and-death evolution process. Results: In this study, we analysed the evolution of this gene cluster in several bat species, belonging to the Yangochiroptera and Yinpterochiroptera sub-orders. Detailed analysis shows a conserved synteny and a gene expansion and loss history. Phylogenetic analysis showed that bats have GBPs 1,2 and 4-6. GBP2 has been lost in several bat families, being present only in Hipposideidae and Pteropodidae. GBPs1, 4 and 5 are present mostly as single-copy genes in all families but have suffered duplication events, particularly in Myotis myotis and Eptesicus fuscus. Most interestingly, we demonstrate that GBP6 duplicated in a Chiroptera ancestor species originating two genes, which we named GBP6a and GBP6b, with different subsequent evolutionary histories. GBP6a underwent several duplication events in all families while GBP6b is present as a single copy gene and has been lost in Pteropodidae, Miniopteridae and Desmodus rotundus, a Phyllostomidae. With 14 and 15 GBP genes, Myotis myotis and Eptesicus fuscus stand out as having far more copies than all other studied bat species. Antagonistically, Pteropodidae have the lowest number of GBP genes in bats. Conclusion: Bats are important reservoirs of viruses, many of which have become zoonotic diseases in the last decades. Further functional studies on bats GBPs will help elucidate their function, evolutionary history, and the role of bats as virus reservoirs.
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Pinheiro, Ana, J. Ricardo Borges, João Vasco Côrte-Real, and Pedro J. Esteves. "Evolution of guanylate binding protein genes shows a remarkable variability within bats (Chiroptera)." Frontiers in Immunology 15 (July 10, 2024): 1329098. https://doi.org/10.5281/zenodo.13435572.
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(Uploaded by Plazi for the Bat Literature Project) Background: GBPs (guanylate binding proteins), an evolutionary ancient protein family, play a key role in the host's innate immune response against bacterial, parasitic and viral infections. In Humans, seven GBP genes have been described (GBP1-7). Despite the interest these proteins have received over the last years, evolutionary studies have only been performed in primates, Tupaia and rodents. These have shown a pattern of gene gain and loss in each family, indicative of the birth-and-death evolution process. Results: In this study, we analysed the evolution of this gene cluster in several bat species, belonging to the Yangochiroptera and Yinpterochiroptera sub-orders. Detailed analysis shows a conserved synteny and a gene expansion and loss history. Phylogenetic analysis showed that bats have GBPs 1,2 and 4-6. GBP2 has been lost in several bat families, being present only in Hipposideidae and Pteropodidae. GBPs1, 4 and 5 are present mostly as single-copy genes in all families but have suffered duplication events, particularly in Myotis myotis and Eptesicus fuscus. Most interestingly, we demonstrate that GBP6 duplicated in a Chiroptera ancestor species originating two genes, which we named GBP6a and GBP6b, with different subsequent evolutionary histories. GBP6a underwent several duplication events in all families while GBP6b is present as a single copy gene and has been lost in Pteropodidae, Miniopteridae and Desmodus rotundus, a Phyllostomidae. With 14 and 15 GBP genes, Myotis myotis and Eptesicus fuscus stand out as having far more copies than all other studied bat species. Antagonistically, Pteropodidae have the lowest number of GBP genes in bats. Conclusion: Bats are important reservoirs of viruses, many of which have become zoonotic diseases in the last decades. Further functional studies on bats GBPs will help elucidate their function, evolutionary history, and the role of bats as virus reservoirs.
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Pinheiro, Ana, J. Ricardo Borges, João Vasco Côrte-Real, and Pedro J. Esteves. "Evolution of guanylate binding protein genes shows a remarkable variability within bats (Chiroptera)." Frontiers in Immunology 15 (July 17, 2024): 1329098. https://doi.org/10.5281/zenodo.13435572.
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(Uploaded by Plazi for the Bat Literature Project) Background: GBPs (guanylate binding proteins), an evolutionary ancient protein family, play a key role in the host's innate immune response against bacterial, parasitic and viral infections. In Humans, seven GBP genes have been described (GBP1-7). Despite the interest these proteins have received over the last years, evolutionary studies have only been performed in primates, Tupaia and rodents. These have shown a pattern of gene gain and loss in each family, indicative of the birth-and-death evolution process. Results: In this study, we analysed the evolution of this gene cluster in several bat species, belonging to the Yangochiroptera and Yinpterochiroptera sub-orders. Detailed analysis shows a conserved synteny and a gene expansion and loss history. Phylogenetic analysis showed that bats have GBPs 1,2 and 4-6. GBP2 has been lost in several bat families, being present only in Hipposideidae and Pteropodidae. GBPs1, 4 and 5 are present mostly as single-copy genes in all families but have suffered duplication events, particularly in Myotis myotis and Eptesicus fuscus. Most interestingly, we demonstrate that GBP6 duplicated in a Chiroptera ancestor species originating two genes, which we named GBP6a and GBP6b, with different subsequent evolutionary histories. GBP6a underwent several duplication events in all families while GBP6b is present as a single copy gene and has been lost in Pteropodidae, Miniopteridae and Desmodus rotundus, a Phyllostomidae. With 14 and 15 GBP genes, Myotis myotis and Eptesicus fuscus stand out as having far more copies than all other studied bat species. Antagonistically, Pteropodidae have the lowest number of GBP genes in bats. Conclusion: Bats are important reservoirs of viruses, many of which have become zoonotic diseases in the last decades. Further functional studies on bats GBPs will help elucidate their function, evolutionary history, and the role of bats as virus reservoirs.
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Cui, Wen, Elisabeth Braun, Wei Wang, et al. "Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins." Proceedings of the National Academy of Sciences 118, no. 15 (2021): e2022269118. http://dx.doi.org/10.1073/pnas.2022269118.
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Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP51–486), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP51–486 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.
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Liang, Hai Po H., Edward J. Kerschen, Irene Hernandez, et al. "EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice." Blood 125, no. 18 (2015): 2845–54. http://dx.doi.org/10.1182/blood-2014-11-610717.
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Abstract Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow–derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses.
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Zhu, Liangyu, Hanxin Wu, Li Peng, et al. "CD4+ Effective Memory T Cell Markers GBP2 and LAG3 Are Risk Factors for PTB and COVID-19 Infection: A Study Integrating Single-Cell Expression Quantitative Trait Locus and Mendelian Randomization Analyses." International Journal of Molecular Sciences 25, no. 18 (2024): 9971. http://dx.doi.org/10.3390/ijms25189971.
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Observational studies indicate that variations in peripheral blood mononuclear cell (PBMC) subsets are associated with an increased risk of pulmonary tuberculosis (PTB) and coronavirus disease 2019 (COVID-19), but causal validation is lacking. Here, we combined single-cell expression quantitative trait locus (sc-eQTL) and two-sample mendelian randomization (MR) analyses to elucidate the causal relationship between PBMC subsets and the occurrence of PTB and COVID-19 and verified by RT-qPCR. We observed an increase in the CD4+ Effective Memory T Cell (CD4+ TEM) cluster in both PTB and COVID-19 patients according to the single-cell transcriptional landscape of PBMC. Through MR analysis using an inverse variance weighted (IVW) method, we found strong evidence of positive correlations between CD4+ TEM cell markers (GBP2, TRAV1-2, and ODF2L) and PTB, and between markers (LAG3 and SLFN5) and COVID-19, especially highlighted by lead eQTL-SNPs of GBP2 (rs2256752, p = 4.76321 × 10−15) and LAG3 (rs67706382, p = 6.16× 10−16). Similar results were observed in validation sets, and no pleiotropy was detected in sensitivity analyses including weighted median (WM), MR-Egger, MR-pleiotropy residual sum and outlier, and leave-one-out analyses (all p > 0.05). We visualized the colocalization of marker-eQTLs and markers of PTB and COVID-19 genome-wide association study (GWAS) associations. Based on CellChat analyses, monocytes communicated predominantly with CD4+ TEM cells positively expressing PTB markers (GBP2, TRAV1-2, and ODF2L) and COVID-19 markers (LAG3 and SLFN5) in both PTB and COVID-19. Our data suggest a causal effect between two key CD4+ TEM cell markers (GBP2 and LAG3) and the risk for PTB and COVID-19 infection. Our findings provide novel insights into the biological mechanism for PTB and COVID-19 infection, but future single-cell studies are necessary to further enhance understanding of this find.
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Yu, Shuye, Xiaoting Yu, Lili Sun, et al. "GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway." Oncogene 39, no. 27 (2020): 5042–55. http://dx.doi.org/10.1038/s41388-020-1348-7.
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Niedelman, Wendy, Joris K. Sprokholt, Barbara Clough, Eva-Maria Frickel, and Jeroen P. J. Saeij. "Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication." Infection and Immunity 81, no. 12 (2013): 4341–49. http://dx.doi.org/10.1128/iai.00416-13.
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ABSTRACTThe intracellular protozoan parasiteToxoplasma gondiiis a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance toToxoplasmais dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance toToxoplasmain primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.
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Yu, Shuye, and Ming Li. "CSIG-20. GBP2 ENHANCES GLIOBLASTOMA INVASION THROUGH STAT3/FIBRONECTION PATHWAY." Neuro-Oncology 20, suppl_6 (2018): vi47. http://dx.doi.org/10.1093/neuonc/noy148.186.
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Ahmetoglu, Derin, Haoyi Zheng, Aaron Swart, Hua Zhu, and Ming Li. "Multifaceted Roles of Guanylate-Binding Proteins in Cancer." International Journal of Molecular Sciences 26, no. 12 (2025): 5477. https://doi.org/10.3390/ijms26125477.
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Guanylate-binding proteins (GBPs), encompassing GBP1 through GBP7 in humans, are interferon-inducible large GTPases of the dynamin superfamily, renowned for their pivotal roles in cell-autonomous immunity against intracellular pathogens such as viruses, bacteria, and protozoa. By recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), GBPs orchestrate lysosomal targeting, regulate inflammatory cascades, and modulate apoptosis to protect host tissues from immune-mediated damage. Beyond their foundational roles in immunity, GBPs exhibit context-dependent effects in human cancer, promoting malignancy in some tumors through enhanced immune signaling, inhibition of apoptosis, and resistance to therapies, or suppressing tumor growth through immune activation and cell cycle regulation. This comprehensive review explores the structural intricacies, immune functions, and multifaceted contributions of human GBPs to cancer, delving into their molecular mechanisms, prognostic potential, and therapeutic implications. We incorporate the latest insights to highlight how understanding GBP regulation could reshape cancer treatment strategies.
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Lu, Yen-Yun, and Heike Krebber. "Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1." International Journal of Molecular Sciences 22, no. 20 (2021): 11275. http://dx.doi.org/10.3390/ijms222011275.
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Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways.
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Kotov, Dmitri I., Jason S. Mitchell, Thomas Pengo, et al. "TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2." Journal of Immunology 202, no. 9 (2019): 2535–45. http://dx.doi.org/10.4049/jimmunol.1801609.
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Martínez-Lumbreras, Santiago, Valerio Taverniti, Silvia Zorrilla, Bertrand Séraphin, and José Manuel Pérez-Cañadillas. "Gbp2 interacts with THO/TREX through a novel type of RRM domain." Nucleic Acids Research 44, no. 1 (2015): 437–48. http://dx.doi.org/10.1093/nar/gkv1303.
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Niu, Pengxia, Sang-Wook Kim, Won-Il Kim, and Kwan-Suk Kim. "Association analyses of DNA polymorphisms in immune-related candidate genes GBP1, GBP2, CD163, and CD169 with porcine growth and meat quality traits." Journal of Biomedical Research 16, no. 2 (2015): 40–46. http://dx.doi.org/10.12729/jbr.2015.16.2.040.
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Qin, Aiping, De-Hua Lai, Weijun Huang та ін. "Bone Marrow-Derived MSCs Stimulated by IFN-γ Inhibited the Growth of ToxoplasmaGondii Via up-Regulation of GBP1". Blood 124, № 21 (2014): 5143. http://dx.doi.org/10.1182/blood.v124.21.5143.5143.
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Abstract Background Mesenchymal stromal cells (MSCs) are a heterogeneous cell population endowed with multi-lineage differentiation potential and extensive immunomodulatory properties. MSCs have been successfully used for prevention and treatment of immune disorders such as graft-versus-host disease. Emerging preclinical studies suggest that MSCs might also protect against infectious challenge. Aims This study aimed to rule out the potential mechanism of human MSCs against Toxoplasma gondii (T. gondii). Methods Human bone marrow-derived MSCs (hMSCs) were pretreated for 24h with a series of concentrations of IFN-γ and then infected with T. gondii strains of variant virulences (virulent RH and avirulent ME49). RNA-seq and westernblots were used to analyze gene and protein expression patterns of hMSCs in IFN-γ-stimulated and unstimulated conditions. The intracellular parasites (with fluorescence labeled) were counted microscopically at multiple time points postinfection. The short hairpin RNA (shRNA) expression was used to generate RNAi of GBP-1, GBP-2 and GBP-5. Results Human MSCs stimulated with IFN-γ were capable to inhibit the growth of T. gondii (eg: at IFN-γ 10ng/ml, the inhibition rates are 26.5% (RH) and 37.5% (ME49) 12hr postinfection) in a dose-dependent manner. Compared with the unstimulated MSCs (controls), IFN-γ treatment at 5, 10, 20ng/ml inhibited T. gondii (ME49) growth by percent of 27.1±7.9, 37.5±6.2, 47.0±7.6 (mean±SD, n=4) 12 hr postinfection and the inhibition rates are 54.5±2.1%, 62.5±4.9% and 78.5±2.1 at 24 hr postinfection, respectively. After 48 hr postinfection, the ratio between parasites per parasitophorous vacuole (PV) containing rosettes and single paraites in IFN-γ-stimulated MSCs was significantly reduced compared with that in the unstimulated MSCs (p<0.01, p<0.01, p<0.001 for ME49 at IFN-γ 5, 10, 20ng/ml, respectively). Furthermore, There was no significant effect of conditioned medium (CM) from IFN-γ-stimulated MSCs on T. gondii growth in comparison with CM from unstimulated MSCs (p=0.74 for RH and p=0.69 for ME49). We observed that the resistance in hMSCs does not depend on IDO (p=0.85 for RH and p=0.79 for ME49). RNA-seq data showed that IFN-γ-inducible p65 guanylate-binding proteins (GBPs) might play pivotal roles in the inhibition of T. gondii growth. Reads per kilobase-pairs per million (RPKM) mean values of GBP1, 2, 5 in IFN-γ-stimulated MSCs are 1093.3, 443.3, 348.2, respectively. By RNAi knockdown, the results showed that silencing of GBP1 (but not GBP2, GBP5) in hMSCs resulted in recovery of T. gondii growth inhibition at 12 hr and 24 hr postinfection (p<0.05 and p<0.001 for ME49). Conclusion: Human MSCs pre-stimulated with IFN-γ inhibited the growth of T. gondii in a dose-dependent manner via up-regulation of GBP-1 expression. Disclosures Liu: the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding.
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Zhao, Xiaoyu, Bocheng Yin, and Sarah E. Ewald. "Cell death effectors are recruited to Toxoplasma gondii parasite vacuoles targeted by interferon-inducible GTPases in infected dendritic cells." Journal of Immunology 206, no. 1_Supplement (2021): 110.04. http://dx.doi.org/10.4049/jimmunol.206.supp.110.04.
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Abstract Toxoplasma gondii is an obligate intracellular pathogen whose ability to grow and evade cell autonomous immunity depends on the parasitophorous vacuole membrane (PVM). The PVM forms from the host plasma membrane during invasion and is maintained by parasite effectors. Interferon-inducible GTPases (IIGs) are central in parasite clearance, however, the precise mechanism linking IIG attack of the PVM, parasite killing and inflammatory host cell death is not clear. To identify host and parasite proteins recruited to the PVM, we used Automated Spatially Targeted Optical Micro Proteomics (AutoSTOMP), a novel discovery technique that uses a confocal microscope to visualize and photo-label proteins for identification by LC-MS. Using IFNγ to induce IIG attack of the PVM and the TLR2 ligand Pam3CSK4 to upregulate inflammasome components we examined protein recruitment to the PVM in BMDCs. AutoSTOMP identified over 300 proteins differentially enriched near the PVM of unprimed, TLR2, IFNγ and IFNγ+TLR2 treated BMDCs. To identify candidate regulators of parasite clearance, we selectively purified proteins on the PVMs coated with IIG protein GBP2. We identified the inflammasome components caspase-1 and ASC as well as the apoptotic caspases-3 and -6 on GBP2-coated PVM. This was consistent with the observation that IFNγ priming was sufficient for host cell death and parasite restriction. BMDC death was partially dependent on the Aim2, ASC, Caspase1/11 and gasdermin D, however, blocking the inflammasome didn’t impair parasite restriction. By contrast, iNOS inhibitor, was sufficient to partially rescue parasite growth. In summary, we report a new tool to study the PVM proteome and identify regulators of parasite clearance and host cell death.
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Huang, Zhijian, Yunyun Han, and Xiaoting Qiu. "Abstract P2-04-26: Predicting the prognosis and immunotherapeutic response of triple-negative breast cancer by constructing a prognostic model based on CD8T cell-related immune genes." Clinical Cancer Research 31, no. 12_Supplement (2025): P2–04–26—P2–04–26. https://doi.org/10.1158/1557-3265.sabcs24-p2-04-26.
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Abstract Background: triple-negative breast cancer (TNBC) posed significant challenges in terms of treatment efficacy. CD8+ T cells, pivotal immune cells, can be effectively analyzed for gene expression differentials across diverse cell populations owing to the rapid advancements in sequencing technology. Leveraging these genes, our objective was to develop a prognostic model that accurately predicted the prognosis of TNBC patients and their responsiveness to immunotherapy. Methods: The sampl e information and clinical data of triple-negative breast cancer (TNBC) were sourced from the TCGA database and METABRIC database. In the initial stage, we identified 67 differentially expressed genes associated with immune response in CD8+ T cells. Subsequently, we narrowed down our focus to three key genes: CXCL13, GBP2, and GZMB, which were utilized for constructing our prognostic model. The accuracy of the model was assessed using validation set data and receiver operating characteristic (ROC) curves. Furthermore, we employed various methods including KEGG pathway analysis, immune infiltration analysis, and correlation analysis with CD274 to explore the model's predictive efficacy in immunotherapeutic responses. Additionally, we investigated the potential underlying biological pathways that contribute to divergent treatment responses. Results: In the initial stage, we identified 67 differentially expressed genes associated with immune response in CD8+ T cells. Subsequently, we narrowed down our focus to three key genes: CXCL13, GBP2, and GZMB, which were utilized for constructing our prognostic model. We successfully developed a prognostic model capable of predicting the prognosis of TNBC patients. The area under the curve (AUC) values for 1, 3, and 5-year survival predictions were determined to be 0.618, 0.652, and 0.826, respectively. Employing this risk model, we stratified the samples into two distinct groups: high-risk and low-risk group. Through KEGG enrichment analysis, we observed that the high-risk group predominantly exhibited enrichment in metabolic-related pathways, such as drug metabolism and chlorophyll metabolism, whereas the low-risk group demonstrated significant enrichment in cytokine pathways. Furthermore, immune landscape analysis revealed noteworthy variations between CD274 expression and risk scores, indicating that our model effectively predicted the response to immune-based treatments in patients. Conclusion: In conclusion, our study demonstrated the potential of CXCL13, GBP2, and GZMB as prognostic indicators for clinical outcomes and immunotherapy response in patients with triple-negative breast cancer. These findings provided valuable insights and present a novel avenue for immunotherapeutic approaches targeting triple-negative breast cancer. Citation Format: Zhijian Huang, Yunyun Han, Xiaoting Qiu. Predicting the prognosis and immunotherapeutic response of triple-negative breast cancer by constructing a prognostic model based on CD8T cell-related immune genes [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-26.
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Zakharova, M. V., A. V. Dyomina, A. A. Kovalenko, O. E. Zubareva, A. M. Ischenko, and A. V. Zaitsev. "Anakinra Promotes M2 Microglia Activation during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy." Российский физиологический журнал им И М Сеченова 110, no. 3 (2024): 424–44. http://dx.doi.org/10.31857/s0869813924030074.
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Astrocytes and microglia and their polarization are thought to contribute to the progression of epilepsy. One of the processes affecting polarization is neuroinflammation, which plays an important role in epileptogenesis. However, the specific mechanisms of its involvement in shifting the pro- and anti-inflammatory reactivation of astro- and microglia have not been clarified. In this study, we examined the effect of 7-day interleukin-1 receptor antagonist (anakinra) administration on glial cell polarization during the latent phase of the lithium-pilocarpine model in 7-week-old male Wistar rats. In temporal cortex, dorsal and ventral hippocampus the mRNA expression levels of the following genes were analyzed: (i) markers of astroglia (S100b) and microglia (Aif1) activation, (ii) astrocytic proteins involved in glutamate transport and metabolism (Slc1a3, Glul, Gja1), (iii) pro-inflammatory pathway interleukin-1β (Nlrp3, Il1b, Il1rn) and transforming growth factor β1 (Tgfb1), (iv) markers of astroglia polarization (Lcn2, S100a10, Gbp2, Ptx3), and (v) microglia polarization (Nos2 and Arg1). The mRNA expression levels of S100b and Aif1 were significantly increased, and anakinra administration did not reduce their overexpression. This indicates reactivation of astroglia and microglia regardless of the anakinra administered. The expression of Slc1a3, Glul, and Gja1 genes increased in the hippocampus; anakinra administration did not affect their hyperexpression, but promoted increased expression of Gja1 in the temporal cortex. The mRNA production of Lcn2, S100a10, Gbp2, Ptx3, Nlrp3, Il1b, Il1rn and Tgfb1 increased in all structures. Administration of anakinra reduced the gene expression of Il1b. Among the markers of microglia polarization, downregulation of Arg1 expression in the dorsal hippocampus and Nos2 expression in the temporal cortex was detected. Anakinra administration enhanced the decrease in Nos2 expression and restored the level of Arg1 expression to control values. Thus, anakinra administration did not affect the intensity of glial cell reactivation, but improved M2 reactivation of microglia.
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Tarhoni, I., C. Fhied, J. A. Borgia, M. J. Fidler, M. Batus, and P. Bonomi. "Novel Autoantibodies Biomarkers Panel to Prognosticate the Clinical Outcomes in Advanced-stage NSCLC Patients Receiving Anti PD-1/PD-L1 Immunotherapy." American Journal of Clinical Pathology 154, Supplement_1 (2020): S142. http://dx.doi.org/10.1093/ajcp/aqaa161.311.
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Abstract Introduction/Objective Lung cancer is the leading cause of cancer-related deaths worldwide, with a majority of cases detected at a non-resectable advanced stage. Current anti PD-1/-L1 therapy has reformed cancer treatment strategies with remarkable clinical outcomes in non-small cell lung cancer (NSCLC). However, the overall response rate is still marginal, demonstrating the need for biomarkers predictive of response. The objective of this study is to develop a serum based panel to prognosticate clinical response in advanced NSCLC patients receiving anti PD-1/-L1 therapy. Methods Pooled sera from two response groups (Poor response, n=20, overall survival &lt; 12 months; Good response, n=20, overall survival &gt; 12 months) were evaluated via the HuProt™ Human Proteome Microarray (CDI laboratories, Baltimore, MD) to identify expressed neoantigens. Recombinant proteins representative to identified neoantigens along with their corresponding antibodies, were commercially acquired to develop a robust 13-plex bead- based immunoassay to evaluate the autoantibodies in pretreatment sera from 125 advanced-stage NSCLC patients. Finally, levels of autoantibodies were correlated to clinical outcome, including progression free survival (PFS), overall survival (OS) and grade III adverse events. Results Low baseline levels of ZNF695, MCM4, PRMT2, FGD3, GTF2A1, GLUL, CDCA3, ZNF277, GARS, GBP2, UBL7, and ASNA1 autoantibodies were found to be associated with a longer PFS (all p-values &lt; 0.01), whereas increased levels were associated with a poor PFS outcome (0.06, HR=0.66, 95% CI). Low levels of ZNF695, MCM4, PRMT2, FGD3, GARS, GBP2, and UBL7 autoantibodies were associated with favorable OS (all p-values &lt; 0.01). Conclusion In this study we demonstrated that serum autoantibodies have great promise to serve as a prognostic tool for immunotherapy response. We successfully developed a high performance multiplexed serum based assay to evaluate autoantibodies in an advanced NSCLC patients receiving anti PD-1/-L1 therapy.
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Mori, Gentaro, Hodaka Sasaki, Yasushi Makabe, Masao Yoshinari, and Yasutomo Yajima. "The genes Scgb1a1, Lpo and Gbp2 characteristically expressed in peri-implant epithelium of rats." Clinical Oral Implants Research 27, no. 12 (2015): e190-e198. http://dx.doi.org/10.1111/clr.12601.
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Querl, Luisa, and Heike Krebber. "Defenders of the Transcriptome: Guard Protein-Mediated mRNA Quality Control in Saccharomyces cerevisiae." International Journal of Molecular Sciences 25, no. 19 (2024): 10241. http://dx.doi.org/10.3390/ijms251910241.
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Cell survival depends on precise gene expression, which is controlled sequentially. The guard proteins surveil mRNAs from their synthesis in the nucleus to their translation in the cytoplasm. Although the proteins within this group share many similarities, they play distinct roles in controlling nuclear mRNA maturation and cytoplasmic translation by supporting the degradation of faulty transcripts. Notably, this group is continuously expanding, currently including the RNA-binding proteins Npl3, Gbp2, Hrb1, Hrp1, and Nab2 in Saccharomyces cerevisiae. Some of the human serine–arginine (SR) splicing factors (SRSFs) show remarkable similarities to the yeast guard proteins and may be considered as functional homologues. Here, we provide a comprehensive summary of their crucial mRNA surveillance functions and their implications for cellular health.
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Roy, Sayantan, Bing Wang, Yuan Tian, and Qian Yin. "Structural and biochemical characterization of an interferon-inducible GTPase, human guanylate binding protein 2 (GBP2)." Acta Crystallographica Section A Foundations and Advances 78, a1 (2022): a36. http://dx.doi.org/10.1107/s2053273322099636.
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Rahvar, Farzaneh, Mahdieh Salimi, and Hossein Mozdarani. "Study of GBP2 Gene Expression and Its Promoter Methylation Pattern in Tumors of Breast Cancer Patients." Multidisciplinary Cancer Investigation 1, Supplementary 1 (2017): 0. http://dx.doi.org/10.21859/mci-supp-04.
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Côrte-Real, João Vasco, Hanna-Mari Baldauf, José Melo-Ferreira, Joana Abrantes, and Pedro José Esteves. "Evolution of Guanylate Binding Protein (GBP) Genes in Muroid Rodents (Muridae and Cricetidae) Reveals an Outstanding Pattern of Gain and Loss." Frontiers in Immunology 13 (February 9, 2022). http://dx.doi.org/10.3389/fimmu.2022.752186.
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Guanylate binding proteins (GBPs) are paramount in the host immunity by providing defense against invading pathogens. Multigene families related to the immune system usually show that the duplicated genes can either undergo deletion, gain new functions, or become non-functional. Here, we show that in muroids, the Gbp genes followed an unusual pattern of gain and loss of genes. Muroids present a high diversity and plasticity regarding Gbp synteny, with most species presenting two Gbp gene clusters. The phylogenetic analyses revealed seven different Gbps groups. Three of them clustered with GBP2, GBP5 and GBP6 of primates. Four new Gbp genes that appear to be exclusive to muroids were identified as Gbpa, b, c and d. A duplication event occurred in the Gbpa group in the common ancestor of Muridae and Cricetidae (~20 Mya), but both copies were deleted from the genome of Mus musculus, M. caroli and Cricetulus griseus. The Gbpb gene emerged in the ancestor of Muridae and Cricetidae and evolved independently originating Gbpb1 in Muridae, Gbpb2 and Gbpb3 in Cricetidae. Since Gbpc appears only in three species, we hypothesize that it was present in the common ancestor and deleted from most muroid genomes. The second Gbp gene cluster, Gbp6, is widespread across all muroids, indicating that this cluster emerged before the Muridae and Cricetidae radiation. An expansion of Gbp6 occurred in M. musculus and M. caroli probably to compensate the loss of Gbpa and b. Gbpd is divided in three groups and is present in most muroids suggesting that a duplication event occurred in the common ancestor of Muridae and Cricetidae. However, in Grammomys surdaster and Mus caroli, Gbpd2 is absent, and in Arvicanthis niloticus, Gbpd1 appears to have been deleted. Our results further demonstrated that primate GBP1, GBP3 and GBP7 are absent from the genome of muroids and showed that the Gbp gene annotations in muroids were incorrect. We propose a new classification based on the phylogenetic analyses and the divergence between the groups. Extrapolations to humans based on functional studies of muroid Gbps should be re-evaluated. The evolutionary analyses of muroid Gbp genes provided new insights about the evolution and function of these genes.
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Place, David E., R. K. Subbarao Malireddi, Jieun Kim, Peter Vogel, Masahiro Yamamoto, and Thirumala-Devi Kanneganti. "Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins." Nature Communications 12, no. 1 (2021). http://dx.doi.org/10.1038/s41467-020-20807-8.
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AbstractChronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferon-stimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. We show that mice deficient in IFN signaling components including IFN alpha and beta receptor 1 (IFNAR1), interferon regulatory factor 1 (IRF1), IRF9, and STAT1 each have reduced bone density and increased osteoclastogenesis compared to wild type mice. The IFN-inducible guanylate-binding proteins (GBPs) on mouse chromosome 3 (GBP1, GBP2, GBP3, GBP5, GBP7) are required to negatively regulate age-associated bone loss and osteoclastogenesis. Mechanistically, GBP2 and GBP5 both negatively regulate in vitro osteoclast differentiation, and loss of GBP5, but not GBP2, results in greater age-associated bone loss in mice. Moreover, mice deficient in GBP5 or chromosome 3 GBPs have greater LPS-mediated inflammatory bone loss compared to wild type mice. Overall, we find that GBP5 contributes to restricting age-associated and inflammation-induced bone loss by negatively regulating osteoclastogenesis.
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Valeva, Stanimira V., Manon Degabriel, Fanny Michal, et al. "Comparative study of GBP recruitment on two cytosol-dwelling pathogens, Francisella novicida and Shigella flexneri highlights differences in GBP repertoire and in GBP1 motif requirements." Pathogens and Disease, April 3, 2023. http://dx.doi.org/10.1093/femspd/ftad005.
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Abstract Guanylate-Binding Proteins are interferon-inducible GTPases that play a key role in cell autonomous responses against intracellular pathogens. Despite sharing high sequence similarity, subtle differences among GBPs translate into functional divergences that are still largely not understood. A key GBP feature is the formation of supramolecular GBP complexes on the bacterial surface. Such complexes are observed when GBP1 binds lipopolysaccharide (LPS) from Shigella and Salmonella and further recruits GBP2-4. Here, we compared GBP recruitment on two cytosol-dwelling pathogens, Francisella novicida and S. flexneri. F. novicida was coated by GBP1 and GBP2 and to a lower extent by GBP4 in human macrophages. Contrary to S. flexneri, F. novicida was not targeted by GBP3, a feature independent of T6SS effectors. Multiple GBP1 features were required to promote targeting to F. novicida while GBP1 targeting to S. flexneri was much more permissive to GBP1 mutagenesis suggesting that GBP1 has multiple domains that cooperate to recognize F. novicida atypical LPS. Altogether our results indicate that the repertoire of GBPs recruited onto specific bacteria is dictated by GBP-specific features and by specific bacterial factors that remain to be identified.
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Dickinson, Mary S., Miriam Kutsch, Linda Sistemich, et al. "LPS-aggregating proteins GBP1 and GBP2 are each sufficient to enhance caspase-4 activation both in cellulo and in vitro." Proceedings of the National Academy of Sciences 120, no. 15 (2023). http://dx.doi.org/10.1073/pnas.2216028120.
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The gamma-interferon (IFNγ)-inducible guanylate-binding proteins (GBPs) promote host defense against gram-negative cytosolic bacteria in part through the induction of an inflammatory cell death pathway called pyroptosis. To activate pyroptosis, GBPs facilitate sensing of the gram-negative bacterial outer membrane component lipopolysaccharide (LPS) by the noncanonical caspase-4 inflammasome. There are seven human GBP paralogs, and it is unclear how each GBP contributes to LPS sensing and pyroptosis induction. GBP1 forms a multimeric microcapsule on the surface of cytosolic bacteria through direct interactions with LPS. The GBP1 microcapsule recruits caspase-4 to bacteria, a process deemed essential for caspase-4 activation. In contrast to GBP1, closely related paralog GBP2 is unable to bind bacteria on its own but requires GBP1 for direct bacterial binding. Unexpectedly, we find that GBP2 overexpression can restore gram-negative-induced pyroptosis in GBP1 KO cells, without GBP2 binding to the bacterial surface. A mutant of GBP1 that lacks the triple arginine motif required for microcapsule formation also rescues pyroptosis in GBP1 KO cells, showing that binding to bacteria is dispensable for GBPs to promote pyroptosis. Instead, we find that GBP2, like GBP1, directly binds and aggregates “free” LPS through protein polymerization. We demonstrate that supplementation of either recombinant polymerized GBP1 or GBP2 to an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation. This provides a revised mechanistic framework for noncanonical inflammasome activation where GBP1 or GBP2 assembles cytosol-contaminating LPS into a protein-LPS interface for caspase-4 activation as part of a coordinated host response to gram-negative bacterial infections.
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Marinho, Fabio V., Camila Brito, Ana Carolina V. S. C. de Araujo, and Sergio C. Oliveira. "Guanylate-binding protein-5 is involved in inflammasome activation by bacterial DNA but only the cooperation of multiple GBPs accounts for control of Brucella abortus infection." Frontiers in Immunology 15 (February 8, 2024). http://dx.doi.org/10.3389/fimmu.2024.1341464.
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IntroductionGuanylate-binding proteins (GBPs) are produced in response to pro-inflammatory signals, mainly interferons. The most studied cluster of GBPs in mice is on chromosome 3. It comprises the genes for GBP1-to-3, GBP5 and GBP7. In humans, all GBPs are present in a single cluster on chromosome 1. Brucella abortus is a Gram-negative bacterium known to cause brucellosis, a debilitating disease that affects both humans and animals. Our group demonstrated previously that GBPs present on murine chromosome 3 (GBPchr3) is important to disrupt Brucella-containing vacuole and GBP5 itself is important to Brucella intracellular LPS recognition. In this work, we investigated further the role of GBPs during B. abortus infection.Methods and resultsWe observed that all GBPs from murine chromosome 3 are significantly upregulated in response to B. abortus infection in mouse bone marrow-derived macrophages. Of note, GBP5 presents the highest expression level in all time points evaluated. However, only GBPchr3-/- cells presented increased bacterial burden compared to wild-type macrophages. Brucella DNA is an important Pathogen-Associated Molecular Pattern that could be available for inflammasome activation after BCV disruption mediated by GBPs. In this regard, we observed reduced IL-1β production in the absence of GBP2 or GBP5, as well as in GBPchr3-/- murine macrophages. Similar result was showed by THP-1 macrophages with downregulation of GBP2 and GBP5 mediated by siRNA. Furthermore, significant reduction on caspase-1 p20 levels, LDH release and Gasdermin-D conversion into its mature form (p30 N-terminal subunit) was observed only in GBPchr3-/- macrophages. In an in vivo perspective, we found that GBPchr3-/- mice had increased B. abortus burden and higher number of granulomas per area of liver tissue, indicating increased disease severity.Discussion/conclusionAltogether, these results demonstrate that although GBP5 presents a high expression pattern and is involved in inflammasome activation by bacterial DNA in macrophages, the cooperation of multiple GBPs from murine chromosome 3 is necessary for full control of Brucella abortus infection.
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Luo, Yongyang, Hanyong Jin, Je Hyeong Kim, and Jeehyeon Bae. "Guanylate-binding proteins induce apoptosis of leukemia cells by regulating MCL-1 and BAK." Oncogenesis 10, no. 7 (2021). http://dx.doi.org/10.1038/s41389-021-00341-y.
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AbstractInterferon-inducible guanylate-binding proteins (GBPs) are well-known for mediating host-defense mechanisms against cellular pathogens. Emerging evidence suggests that GBPs are also implicated in tumorigenesis; however, their underlying molecular mechanism is still unknown. In this study, we identified that GBP1 and GBP2 interact with MCL-1, the key prosurvival member of the BCL-2 family, via its BH3 domain. GBPs induce caspase-dependent apoptosis in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells, where the proapoptotic BCL-2 member, BAK, is an indispensable mediator. In particular, GBP2 completely inhibited the MCL-1-mediated promotion of the survival of CML cells through competitive inhibition, resulting in BAK liberation from MCL-1. Concurrently, GBP2 dramatically upregulates BAK expression via its inhibition of the PI3K/AKT pathway. Moreover, paclitaxel upregulates GBP2 expression, and paclitaxel-induced apoptotic activity was distinctively compromised by knockout of GBP2 in CML cells. Bioinformatics analyses of leukemia databases revealed that transcripts of GBPs were generally downregulated in leukemia patients and that GBPs were favorable prognosis markers. Thus, these findings provide molecular evidence of GBPs as apoptosis-inducing proteins of leukemia cells and suggest that GBPs are attractive targets for the development of chemotherapeutics.
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Goers, Lisa, Kyungsub Kim, Teagan C. Stedman, et al. "Shigella IpaH9.8 limits GBP1-dependent LPS release from intracytosolic bacteria to suppress caspase-4 activation." Proceedings of the National Academy of Sciences 120, no. 15 (2023). http://dx.doi.org/10.1073/pnas.2218469120.
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Pyroptosis is an inflammatory form of cell death induced upon recognition of invading microbes. During an infection, pyroptosis is enhanced in interferon-gamma-exposed cells via the actions of members of the guanylate-binding protein (GBP) family. GBPs promote caspase-4 (CASP4) activation by enhancing its interactions with lipopolysaccharide (LPS), a component of the outer envelope of Gram-negative bacteria. Once activated, CASP4 promotes the formation of noncanonical inflammasomes, signaling platforms that mediate pyroptosis. To establish an infection, intracellular bacterial pathogens, like Shigella species, inhibit pyroptosis. The pathogenesis of Shigella is dependent on its type III secretion system, which injects ~30 effector proteins into host cells. Upon entry into host cells, Shigella are encapsulated by GBP1, followed by GBP2, GBP3, GBP4, and in some cases, CASP4. It has been proposed that the recruitment of CASP4 to bacteria leads to its activation. Here, we demonstrate that two Shigella effectors, OspC3 and IpaH9.8, cooperate to inhibit CASP4-mediated pyroptosis. We show that in the absence of OspC3, an inhibitor of CASP4, IpaH9.8 inhibits pyroptosis via its known degradation of GBPs. We find that, while some LPS is present within the host cell cytosol of epithelial cells infected with wild-type Shigella, in the absence of IpaH9.8, increased amounts are shed in a GBP1-dependent manner. Furthermore, we find that additional IpaH9.8 targets, likely GBPs, promote CASP4 activation, even in the absence of GBP1. These observations suggest that by boosting LPS release, GBP1 provides CASP4-enhanced access to cytosolic LPS, thus promoting host cell death via pyroptosis.
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Fisch, Daniel, Barbara Clough, Rabia Khan, Lyn Healy, and Eva-Maria Frickel. "Toxoplasma-proximal and distal control by GBPs in human macrophages." Pathogens and Disease 79, no. 9 (2021). http://dx.doi.org/10.1093/femspd/ftab058.
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ABSTRACT Human guanylate binding proteins (GBPs) are key players of interferon–gamma (IFNγ)-induced cell intrinsic defense mechanisms targeting intracellular pathogens. In this study, we combine the well-established Toxoplasmagondii infection model with three in vitro macrophage culture systems to delineate the contribution of individual GBP family members to control this apicomplexan parasite. Use of high-throughput imaging assays and genome engineering allowed us to define a role for GBP1, 2 and 5 in parasite infection control. While GBP1 performs a pathogen-proximal, parasiticidal and growth-restricting function through accumulation at the parasitophorous vacuole of intracellular Toxoplasma, GBP2 and GBP5 perform a pathogen-distal, growth-restricting role. We further find that mutants of the GTPase or isoprenylation site of GBP1/2/5 affect their normal function in Toxoplasma control by leading to mis-localization of the proteins.
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Schelle, Luca, João Vasco Côrte-Real, Sharmeen Fayyaz, et al. "Evolutionary and functional characterization of lagomorph guanylate-binding proteins: a story of gain and loss and shedding light on expression, localization and innate immunity-related functions." Frontiers in Immunology 15 (January 29, 2024). http://dx.doi.org/10.3389/fimmu.2024.1303089.
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Guanylate binding proteins (GBPs) are an evolutionarily ancient family of proteins that are widely distributed among eukaryotes. They belong to the dynamin superfamily of GTPases, and their expression can be partially induced by interferons (IFNs). GBPs are involved in the cell-autonomous innate immune response against bacterial, parasitic and viral infections. Evolutionary studies have shown that GBPs exhibit a pattern of gene gain and loss events, indicative for the birth-and-death model of evolution. Most species harbor large GBP gene clusters that encode multiple paralogs. Previous functional and in-depth evolutionary studies have mainly focused on murine and human GBPs. Since rabbits are another important model system for studying human diseases, we focus here on lagomorphs to broaden our understanding of the multifunctional GBP protein family by conducting evolutionary analyses and performing a molecular and functional characterization of rabbit GBPs. We observed that lagomorphs lack GBP3, 6 and 7. Furthermore, Leporidae experienced a loss of GBP2, a unique duplication of GBP5 and a massive expansion of GBP4. Gene expression analysis by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and transcriptome data revealed that leporid GBP expression varied across tissues. Overexpressed rabbit GBPs localized either uniformly and/or discretely to the cytoplasm and/or to the nucleus. Oryctolagus cuniculus (oc)GBP5L1 and rarely ocGBP5L2 were an exception, colocalizing with the trans-Golgi network (TGN). In addition, four ocGBPs were IFN-inducible and only ocGBP5L2 inhibited furin activity. In conclusion, from an evolutionary perspective, lagomorph GBPs experienced multiple gain and loss events, and the molecular and functional characteristics of ocGBP suggest a role in innate immunity.
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Kohler, Kristin M., Miriam Kutsch, Anthony S. Piro, Graham D. Wallace, Jörn Coers, and Matthew F. Barber. "A Rapidly Evolving Polybasic Motif Modulates Bacterial Detection by Guanylate Binding Proteins." mBio 11, no. 3 (2020). http://dx.doi.org/10.1128/mbio.00340-20.
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ABSTRACT Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri. By swapping this membrane-binding motif between primate GBP orthologs, we found that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World primates. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense. IMPORTANCE Many infectious diseases are caused by microbes that enter and survive within host cells. Guanylate binding proteins (GBPs) are a group of immune proteins which recognize and inhibit a variety of intracellular pathogenic microbes. We discovered that a short sequence within GBPs required for the detection of bacteria, the polybasic motif (PBM), has been rapidly evolving between primate species. By swapping PBMs between primate GBP1 genes, we were able to show that specific sequences can both reduce and improve the ability of GBP1 to target intracellular bacteria. We also show that the ability to envelop bacteria has independently evolved in GBP2 of South American monkeys. Taking the results together, this report illustrates how primate GBPs have adapted to defend against infectious pathogens.