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Yap, Melvyn W., Mark P. Dodding, and Jonathan P. Stoye. "Trim-Cyclophilin A Fusion Proteins Can Restrict Human Immunodeficiency Virus Type 1 Infection at Two Distinct Phases in the Viral Life Cycle." Journal of Virology 80, no. 8 (2006): 4061–67. http://dx.doi.org/10.1128/jvi.80.8.4061-4067.2006.
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ABSTRACT The Trim5α protein from several primates restricts retroviruses in a capsid (CA)-dependent manner. In owl monkeys, the B30.2 domain of Trim5 has been replaced by cyclophilin A (CypA) following a retrotransposition. Restriction of human immunodeficiency virus type 1 (HIV-1) by the resulting Trim5-CypA fusion protein depends on CA binding to CypA, suggesting both that the B30.2 domain might be involved in CA binding and that the tripartite RING motif, B-BOX, and coiled coil (RBCC) motif domain can function independently of the B30.2 domain in restriction. To investigate the potential of RBCCs from other Trims to participate in restricting HIV-1, CypA was fused to the RBCC of Trim1, Trim18, and Trim19 and tested for restriction. Despite low identity within the RBCC domain, all fusion proteins were found to restrict HIV-1 but not the nonbinding G89V mutant, indicating that the overall structure of RBCC and not its primary sequence was important for the restriction function. The critical interaction between CA and Trim-CypA appears to take place soon after viral entry. Quantitative PCR analysis of viral reverse transcriptase products revealed that the different fusion proteins block HIV-1 at two distinct stages of its life cycle, either prior to reverse transcription or just before integration. With Trim1 and Trim18, this timing is dependent on the length of the Trim component of the fusion protein. These observations suggest that restriction factor binding can have different mechanistic consequences.
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Toka, Felix N., Kiera Dunaway, Matylda Mielcarska, Felicia Smaltz, and Magdalena Bossowska-Nowicka. "Expression pattern of TRIM genes in bovine macrophages stimulated with PAMPs." Journal of Immunology 198, no. 1_Supplement (2017): 129.7. http://dx.doi.org/10.4049/jimmunol.198.supp.129.7.
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Abstract In mammals innate immune mechanisms form the first line of defence against invading pathogens. Detection of viruses early in infection relies on intracellular receptors that sense microbial molecular patterns, subsequently leading to gene transcription that eventually produces IFN type I and II. Type I and II IFNs act to prevent replication of viruses. Tripartite Motif-containing (TRIM) proteins belong to a superfamily of RING-domain E3 ubiquitin ligases. They represent a novel class of antiviral molecules involved in innate immunity. These enzymes function in a wide variety of important cellular processes, particularly in innate antiviral response mechanisms. We studied the expression profile of 46 TRIM genes in a bovine macrophage cell line BoMac using RT2 PCR. PAMPs were used to imitate 2 important groups of pathogens. PolyI:C was used in place of viral dsRNA, LPS was used in place of Gram-negative bacteria, Pam3CSK4 was used in place of Gram-positive and negative bacteria, PolyI:C-LyoVec was used in place of viral sRNA and CpG was used in place of bacterial and viral DNA. Of the 46 TRIM genes, only 8 bovine TRIM genes were upregulated following stimulation of BoMac with individual PAMPs. PolyI:C induce upregulation of TRIM21, TRIM25 and TRIM56. All three TRIMs are known for their antiviral activity in human cell lines and mice. Pam3CSK4 and LPS, both upregulated TRIM10. PolyI:C-LyoVec upregulated TRIM9, TRIM40 and TRIM55. TRIM40 is an anti-inflammatory molecule. CpG upregulated TRIM40 and TRIM29. High expression of TRIM29 is regarded as a poor prognostic in many tumors, but no antimicrobial role has been described yet for TRIM29. Data will be discussed in the context of antiviral role of TRIMs in bovine viral infections.
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Sebastian, Sarah, Christian Grütter, Caterina Strambio de Castillia та ін. "An Invariant Surface Patch on the TRIM5α PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding". Journal of Virology 83, № 7 (2009): 3365–73. http://dx.doi.org/10.1128/jvi.00432-08.
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ABSTRACT TRIM5α is a retrovirus restriction factor in the host cell cytoplasm that blocks infection before provirus establishment. Restriction activity requires capsid (CA)-specific recognition by the PRYSPRY domain of TRIM5α. To better understand the restriction mechanism, nine charge-cluster-to-triple-alanine mutants in the TRIM5α PRYSPRY domain were assessed for CA-specific restriction activity. Five mutants distributed along the TRIM5α PRYSPRY primary sequence disrupted restriction activity against N-tropic murine leukemia virus and equine infectious anemia virus. Modeling of the TRIM5α PRYSPRY domain based on the crystal structures of PRYSPRY-19q13.4.1, GUSTAVUS, and TRIM21 identified a surface patch where disruptive mutants clustered. All mutants in this patch retained CA-binding activity, a reticular distribution in the cytoplasm, and steady-state protein levels comparable to those of the wild type. Residues in the essential patch are conserved in TRIM5α orthologues and in closely related paralogues. The same surface patch in the TRIM18 and TRIM20 PRYSPRY domains is the site of mutants causing Opitz syndrome and familial Mediterranean fever. These results indicate that, in addition to CA-specific binding, the PRYSPRY domain possesses a second function, possibly binding of a cofactor, that is essential for retroviral restriction activity by TRIM5α.
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Margalit, Liad, Carmit Strauss, Ayellet Tal, and Sharon Schlesinger. "Trim24 and Trim33 Play a Role in Epigenetic Silencing of Retroviruses in Embryonic Stem Cells." Viruses 12, no. 9 (2020): 1015. http://dx.doi.org/10.3390/v12091015.
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Embryonic stem cells (ESC) have the ability to epigenetically silence endogenous and exogenous retroviral sequences. Trim28 plays an important role in establishing this silencing, but less is known about the role other Trim proteins play. The Tif1 family is a sub-group of the Trim family, which possess histone binding ability in addition to the distinctive RING domain. Here, we have examined the interaction between three Tif1 family members, namely Trim24, Trim28 and Trim33, and their function in retroviral silencing. We identify a complex formed in ESC, comprised of these three proteins. We further show that when Trim33 is depleted, the complex collapses and silencing efficiency of both endogenous and exogenous sequences is reduced. Similar transcriptional activation takes place when Trim24 is depleted. Analysis of the H3K9me3 chromatin modification showed a decrease in this repressive mark, following both Trim24 and Trim33 depletion. As Trim28 is an identified binding partner of the H3K9 methyltransferase ESET, this further supports the involvement of Trim28 in the complex. The results presented here suggest that a complex of Tif1 family members, each of which possesses different specificity and efficiency, contributes to the silencing of retroviral sequences in ESC.
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Rybakowska, Paulina, Nina Wolska, Arkadiusz Klopocki, et al. "Multiple TRIM proteins are targets of autoimmune response in lupus and Sjogren's syndrome. (HUM7P.308)." Journal of Immunology 192, no. 1_Supplement (2014): 184.17. http://dx.doi.org/10.4049/jimmunol.192.supp.184.17.
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Abstract TRIM21 belongs to the large family of tripartite motif containing proteins, and is often targeted by autoantibodies in lupus and Sjogren’s syndrome. Considering the significant protein domain homology between different TRIM proteins, we hypothesized that additional TRIM proteins are targets of autoimmunity. Based on the literature, in this study we investigated autoantibody responses to TRIM38. While 9% of lupus patients (n=149) had anti-TRIM38 antibodies, the incidence in Sjogren’s syndrome patients (n=150) was 12%, and in controls (n=50) it was 4%. With respect to TRIM21, the incidence was 62%, 68%, and 4% respectively. In Sjogren’s syndrome patients, the presence of anti-TRIM38 antibodies was closely associated with the increased severity of dry eye parameters. Epitope mapping studies showed that anti-TRIM21 antibodies reacted with the RING, Coiled coil and PRY-SPRY domains of TRIM21, whereas anti-TRIM38 antibodies reacted only with the Coiled coil and PRY-SPRY domains of TRIM38. All anti-TRIM38 positive patients also had anti-TRIM21 antibodies. Affinity purified anti-TRIM21 antibodies from lupus patients did not immunoprecipitate TRIM38, indicating lack of cross-reactivity at B cell level. However, we observed T cell cross-reactivity between TRIM21298-312 and TRIM38302-316. Our study suggests that immune responses to TRIM proteins can evolve through epitope spreading and contribute towards exacerbating the pathogenesis in autoimmune disorders.
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Agarwal, Neeraj, Sebastien Rinaldetti, Bassem B. Cheikh, et al. "TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer." Proceedings of the National Academy of Sciences 118, no. 38 (2021): e2102423118. http://dx.doi.org/10.1073/pnas.2102423118.
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Bladder cancer (BC) has a 70% telomerase reverse transcriptase (TERT or hTERT in humans) promoter mutation prevalence, commonly at −124 base pairs, and this is associated with increased hTERT expression and poor patient prognosis. We inserted a green fluorescent protein (GFP) tag in the mutant hTERT promoter allele to create BC cells expressing an hTERT-GFP fusion protein. These cells were used in a fluorescence-activated cell sorting–based pooled CRISPR-Cas9 Kinome knockout genetic screen to identify tripartite motif containing 28 (TRIM28) and TRIM24 as regulators of hTERT expression. TRIM28 activates, while TRIM24 suppresses, hTERT transcription from the mutated promoter allele. TRIM28 is recruited to the mutant promoter where it interacts with TRIM24, which inhibits its activity. Phosphorylation of TRIM28 through the mTOR complex 1 (mTORC1) releases it from TRIM24 and induces hTERT transcription. TRIM28 expression promotes in vitro and in vivo BC cell growth and stratifies BC patient outcome. mTORC1 inhibition with rapamycin analog Ridaforolimus suppresses TRIM28 phosphorylation, hTERT expression, and cell viability. This study may lead to hTERT-directed cancer therapies with reduced effects on normal progenitor cells.
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Stevens, Rebecca V., Diego Esposito, and Katrin Rittinger. "Characterisation of class VI TRIM RING domains: linking RING activity to C-terminal domain identity." Life Science Alliance 2, no. 3 (2019): e201900295. http://dx.doi.org/10.26508/lsa.201900295.
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TRIM E3 ubiquitin ligases regulate multiple cellular processes, and their dysfunction is linked to disease. They are characterised by a conserved N-terminal tripartite motif comprising a RING, B-box domains, and a coiled-coil region, with C-terminal domains often mediating substrate recruitment. TRIM proteins are grouped into 11 classes based on C-terminal domain identity. Class VI TRIMs, TRIM24, TRIM33, and TRIM28, have been described as transcriptional regulators, a function linked to their C-terminal plant homeodomain and bromodomain, and independent of their ubiquitination activity. It is unclear whether E3 ligase activity is regulated in family members where the C-terminal domains function independently. Here, we provide a detailed biochemical characterisation of the RING domains of class VI TRIMs and describe the solution structure of the TRIM28 RING. Our study reveals a lack of activity of the isolated RING domains, which may be linked to the absence of self-association. We propose that class VI TRIMs exist in an inactive state and require additional regulatory events to stimulate E3 ligase activity, ensuring that associated chromatin-remodelling factors are not injudiciously degraded.
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Zanchetta, Melania E., Luisa M. R. Napolitano, Danilo Maddalo, and Germana Meroni. "The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1864, no. 10 (2017): 1844–54. http://dx.doi.org/10.1016/j.bbamcr.2017.07.014.
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McAvera, Roisin M., and Lisa J. Crawford. "TIF1 Proteins in Genome Stability and Cancer." Cancers 12, no. 8 (2020): 2094. http://dx.doi.org/10.3390/cancers12082094.
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Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation.
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Herquel, B., K. Ouararhni, K. Khetchoumian, et al. "Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma." Proceedings of the National Academy of Sciences 108, no. 20 (2011): 8212–17. http://dx.doi.org/10.1073/pnas.1101544108.
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Lascano, Josefina, Pradeep D. Uchil, Walther Mothes, and Jeremy Luban. "TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling." Journal of Virology 90, no. 1 (2015): 308–16. http://dx.doi.org/10.1128/jvi.02496-15.
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ABSTRACTHost restriction factor TRIM5 inhibits retroviral transduction in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. However, the restriction mechanism may not be that simple since TRIM5 E3 ubiquitin ligase activity, the proteasome, autophagy, and TAK1-dependent AP-1 signaling have been suggested to contribute to restriction. Here, we show that, among a panel of seven primate and Carnivora TRIM5 orthologues, each of which has potential for potent retroviral restriction activity, all activated AP-1 signaling. In contrast, TRIM family paralogues most closely related to TRIM5 did not. While each primate species has a single TRIM5 gene, mice have at least seven TRIM5 homologues that cluster into two groups, Trim12a, -b, and -c and Trim30a, -b, -c, and -d. The three Trim12 proteins activated innate immune signaling, while the Trim30 proteins did not, though none of the murine Trim5 homologues restricted any of a panel of cloned retroviruses. To determine if any mouse TRIM5 homologues had potential for restriction activity, each was fused to the human immunodeficiency virus type 1 (HIV-1) CA binding protein cyclophilin A (CypA). The three Trim12-CypA fusions all activated AP-1 and restricted HIV-1 transduction, whereas the Trim30-CypA fusions did neither. AP-1 activation and HIV-1 restriction by the Trim12-CypA fusions were inhibited by disruption of TAK1. Overall then, these experiments demonstrate that there is a strong correlation between TRIM5 retroviral restriction activity and the ability to activate TAK1-dependent innate immune signaling.IMPORTANCEThe importance of retroviruses for the evolution of susceptible host organisms cannot be overestimated. Eight percent of the human genome is retrovirus sequence, fixed in the germ line during past infection. Understanding how metazoa protect their genomes from mutagenic retrovirus infection is therefore of fundamental importance to biology. TRIM5 is a cellular protein that protects host genome integrity by disrupting the retroviral capsid as it transports viral nucleic acid to the host cell nucleus. Previous data suggest that innate immune signaling contributes to TRIM5-mediated restriction. Here, we show that activation of innate immune signaling is conserved among primate and carnivore TRIM5 orthologues and among 3 of the 7 mouse Trim5 homologues and that such activity is required for TRIM5-mediated restriction activity.
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Kimura, Tomonori, Ashish Jain, Seong Won Choi, et al. "TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity." Journal of Cell Biology 210, no. 6 (2015): 973–89. http://dx.doi.org/10.1083/jcb.201503023.
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The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.
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Palomba, Tommaso, Giusy Tassone, Carmine Vacca, et al. "Exploiting ELIOT for Scaffold-Repurposing Opportunities: TRIM33 a Possible Novel E3 Ligase to Expand the Toolbox for PROTAC Design." International Journal of Molecular Sciences 23, no. 22 (2022): 14218. http://dx.doi.org/10.3390/ijms232214218.
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The field of targeted protein degradation, through the control of the ubiquitin–proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33. Starting from ELIOT, a case study of the cross-relationship using GRID Molecular Interaction Field (MIF) similarities between TRIM24 and TRIM33 binding sites was selected. Based on the assumption that similar pockets could bind similar ligands and considering that TRIM24 has 12 known co-crystalised ligands, we applied a scaffold-repurposing strategy for the identification of TRIM33 ligands exploiting the scaffold of TRIM24 ligands. We performed a deeper computational analysis to identify pocket similarities and differences, followed by docking and water analysis; selected ligands were synthesised and subsequently tested against TRIM33 via HTRF binding assay, and we obtained the first-ever X-ray crystallographic complexes of TRIM33α with three of the selected compounds.
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Reddi, Tejaswini S., Philipp E. Merkl, So-Yon Lim, Norman L. Letvin, and David M. Knipe. "Tripartite Motif 22 (TRIM22) protein restricts herpes simplex virus 1 by epigenetic silencing of viral immediate-early genes." PLOS Pathogens 17, no. 2 (2021): e1009281. http://dx.doi.org/10.1371/journal.ppat.1009281.
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Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the β- and γ- herpesviruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV-1 infection in humans. Collectively, these results argue that TRIM22 is a novel restriction factor and expand the list of restriction factors functioning in the infected cell nucleus to counter DNA virus infection.
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Lionnard, Loïc, Pauline Duc, Margs S. Brennan, et al. "TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1." Cell Death & Differentiation 26, no. 5 (2018): 902–17. http://dx.doi.org/10.1038/s41418-018-0169-5.
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Li, Xing, Yuan Li, Matthew Stremlau та ін. "Functional Replacement of the RING, B-Box 2, and Coiled-Coil Domains of Tripartite Motif 5α (TRIM5α) by Heterologous TRIM Domains". Journal of Virology 80, № 13 (2006): 6198–206. http://dx.doi.org/10.1128/jvi.00283-06.
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ABSTRACT Tripartite motif 5α (TRIM5α) restricts some retroviruses, including human immunodeficiency virus type 1 (HIV-1), from infecting the cells of particular species. TRIM5α is a member of the TRIM family of proteins, which contain RING, B-box, coiled-coil (CC), and, in some cases, B30.2(SPRY) domains. Here we investigated the abilities of domains from TRIM proteins (TRIM6, TRIM34, and TRIM21) that do not restrict HIV-1 infection to substitute for the domains of rhesus monkey TRIM5α (TRIM5αrh). The RING, B-box 2, and CC domains of the paralogous TRIM6 and TRIM34 proteins functionally replaced the corresponding TRIM5αrh domains, allowing HIV-1 restriction. By contrast, similar chimeras containing the components of TRIM21, a slightly more distant relative of TRIM5, did not restrict HIV-1 infection. The TRIM21 B-box 2 domain and its flanking linker regions contributed to the functional defectiveness of these chimeras. All of the chimeric proteins formed trimers. All of the chimeras that restricted HIV-1 infection bound the assembled HIV-1 capsid complexes. These results indicate that heterologous RING, B-box 2, and CC domains from related TRIM proteins can functionally substitute for TRIM5αrh domains.
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Azuma, Kotaro, and Satoshi Inoue. "Efp/TRIM25 and Its Related Protein, TRIM47, in Hormone-Dependent Cancers." Cells 11, no. 15 (2022): 2464. http://dx.doi.org/10.3390/cells11152464.
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Increasing attention has been paid to the biological roles of tripartite motif-containing (TRIM) family proteins, which typically function as E3 ubiquitin ligases. Estrogen-responsive finger protein (Efp), a member of the TRIM family proteins, also known as TRIM25, was originally identified as a protein induced by estrogen and plays critical roles in promoting endocrine-related cancers, including breast cancer, endometrial cancer, and prostate cancer. The pathophysiological importance of Efp made us interested in the roles of other TRIM family proteins that share a similar structure with Efp. Based on a phylogenetic analysis of the C-terminal region of TRIM family proteins, we focused on TRIM47 as a protein belonging to the same branch as Efp. TRIM47 is a poor prognostic factor in both breast cancer and prostate cancer. Atypical lysine-27-like poly-ubiquitination was involved in the underlying mechanism causing endocrine resistance in breast cancer. We also discuss the functions of Efp and TRIM47 in other types of cancers and innate immunity by introducing substrates the are modified by poly-ubiquitination.
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Jacques, David, Cy Jeffries, Matthew Caines, et al. "TRIM protein domain topology and implications for antiviral immunity." Acta Crystallographica Section A Foundations and Advances 70, a1 (2014): C243. http://dx.doi.org/10.1107/s2053273314097563.
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The tripartite motif (TRIM) proteins are a large family of >100 members, several of which have important roles in antiviral immunity and innate immune signaling. TRIM5α associates with incoming HIV-1 capsids, interfering with controlled disassembly and targeting them for degradation by the proteasome. TRIM21 is a cytosolic antibody receptor, which also targets incoming viral capsids for proteasomal degradation. TRIM25 is also involved in innate immunity, being essential for the ubiquitination of RIG-I. Recent positive selection analysis has predicted another 10 TRIM proteins with antiviral activity. Despite the fact that TRIM5α, 21 and 25 play key roles in antiviral protection, their mechanism of action is incompletely understood. All three proteins share a similar domain architecture, comprising a RING, B Box, coiled coil and PRYSPRY domains. The RING domains are responsible for ubiquitin ligase activity, while the PRYSPRY domains determine target specificity. We have used a combination of crystallography and SAXS to generate the first complete model for a TRIM protein structure. Crystallographic studies of TRIM25 reveal a central elongated coiled-coil domain with an unusual right-handed twist. The dimer formed by the coiled-coil is antiparallel but is followed by additional helices that reverse the direction of the protein chain. This structure suggests that the N-terminal domains of each monomer are separated but the C terminal domains are maintained in proximity. Multi-angle light scattering (MALS), isothermal titration calorimetry (ITC) and SAXS analysis confirms that this dimer structure is present in solution. Furthermore, scattering studies on the tripartite motif of TRIM21, comprising RING, B Box and coiled-coil, demonstrate that the first two domains of each monomer are held 150-200 Å apart. Finally, SAXS measurement of a complex between intact TRIM21 and its ligand, IgG Fc, provides the first empirical structure of a complete TRIM protein.
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Lassot, Iréna, Stéphan Mora, Suzanne Lesage та ін. "The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21". Cell Reports 25, № 9 (2018): 2484–96. http://dx.doi.org/10.1016/j.celrep.2018.11.002.
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Zhang, Wen, Zhengquan Cai, Mingzhu Kong, et al. "Prognostic significance of TRIM28 expression in patients with breast carcinoma." Open Medicine 16, no. 1 (2021): 472–80. http://dx.doi.org/10.1515/med-2021-0263.
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Abstract Background Tripartite motif 28 (TRIM28) plays a role in multiple biological functions. The expression and function of TRIM28 in breast carcinoma (BC) remain unclear. The aim of this study was to explore potential association of TRIM28 with tumor features and survival. Materials and methods Specimens were collected from BC and adjacent normal tissues. Quantitative reverse transcription PCR (RT-qPCR) and immunohistochemistry (IHC) were performed to detect TRIM28 expression. The correlation of TRIM28 with clinicopathological features was evaluated by Chi-square test. The relationship between TRIM28 expression and survival was further analyzed by the Kaplan-Meier and Cox regression method. A receiver operating characteristic (ROC) curve was used to assess the value of TRIM28 in predicting BC. Results In this retrospective research, it was demonstrated that TRIM28 was overexpressed in BC tissues. TRIM28 overexpression was correlated with lymph node metastasis, advanced TNM stage, and poor molecular subtype. The survival analysis showed that overall survival (OS) and progression-free survival (PFS) were significantly shorter in TRIM28-positive group. Moreover, TRIM28 was an independent prognostic factor for BC. And ROC analysis verified the diagnostic role of TRIM28 in BC. Conclusions TRIM28 is overexpressed in BC and might be a promising prognostic and diagnostic biomarker of BC.
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Terui, Yasuhito, Ryoko Kuniyoshi, Yuji Mishima, Yuko Mishima, and Kiyohiko Hatake. "Ubiquitin E3 Ligase, Tripartite Motif Protein 68 (TRIM68) Inhibits TCP-1 b Function by Proteasome-Mediated Degradation and May Overcome Imatinib-Resistance." Blood 114, no. 22 (2009): 3789. http://dx.doi.org/10.1182/blood.v114.22.3789.3789.
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Abstract Abstract 3789 Poster Board III-725 [Background] Imatinib mesylate is effective therapy against Philadelphia chromosome-positive leukemia, but the resistance develops in all phases of the disease. The identification of new proteins induced by imatinib may lead to find the novel potent molecular targets in imatinib-resistant CML. [Methods] K562 cells were treated with or without 1 mM imatinib for 24 hours, and then differential display between them was performed. TRIM68 expression was examined by RT-PCR, and in vivo ubiquitination or sumoylation assay was performed by transfection experiment and Western blot analysis. The substrates for TRIM68 were analyzed by mass spectorometry. [Results] As the results of RNA differential display, we found that the expression of TRIM68 mRNA was increased when the K562 cells were treated with 1 mM imatinib for 24 hours. TRIM68 protein possesses a RING finger domain at its N-terminal site. Since many RING-finger proteins have been identified as E3 ligases for ubiquitination or sumoylation (Meroni G, Diez-Roux G. TRIM/RBCC, a novel class of esingle protein RING finger' E3 ubiquitin ligases. Bioessays 2005; 27: 1147-57.), we examined whether TRIM68 functions as an E3 ligase for ubiquitination or sumoylation. To examine the function of TRIM68 as an E3 ligase, wild type TRIM68 and a RING domain deletion mutant of TRIM68 (TRIM68/¢R) genes were constructed into a mammalian expression vector and they were transfected into MCF7 cells. TRIM68 had auto-ubiquitination activity but not auto-sumoylation activity on the in vivo assays, suggesting that TRIM68 can be an ubiquitin E3 ligase but not sumo ligase. Moreover, wild type TRIM68 promoted the whole ubiqutination in the cells, whereas TRIM68/¢R prevented the ubiquitination inside of the cells. To identify the TRIM68-interacting proteins, we transfected FLAG-tagged wild type TRIM68 gene or B30.2/SPRY domain of TRIM68 gene into MCF7 cells, and immunoprecipitation with FLAG-M2 agarose was performed and mass spectrometric analysis was performed. As the results, we revealed that the members of molecular chaperone T-complex polypeptide 1 (TCP-1) complex, TCP-1 b and heat shock protein 70 (HSP70) interacted with TRIM68 at the B30.2/SPRY domain. Then, we examined whether TCP-1 b is one of the substrates for TRIM68-related ubiqutination. TCP-1 b was ubiquitinated by wild type TRIM68, but not by TRIM68/¢R. Furthermore, the ubiquitination of TCP-1 b was accumulated by the treatment with a proteasome inhibitor MG132. These suggested that TCP-1 b is one of the substrates for TRIM68. [Conclusions] We found that TRIM68 is induced by the treatment with imatinib and functions as an ubiquitin E3 ligase. Furthermore, we identified that TCP-1 b is a substrate of TRIM68. TRIM68 may inhibit the function of TCP-1 b as a chaperone by ubiquitination and proteasome-mediated degradation. TRIM68 is possible for a new target in the imatinib-resistant CML. Disclosures: No relevant conflicts of interest to declare.
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Lu, Hsin-Pin, Chieh-Ju Lin, Wen-Ching Chen, et al. "TRIM28 Regulates Dlk1 Expression in Adipogenesis." International Journal of Molecular Sciences 21, no. 19 (2020): 7245. http://dx.doi.org/10.3390/ijms21197245.
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The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.
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Wang, Zhaofeng, Xiaobo Xu, Wenxiao Tang, Youcai Zhu, Jichao Hu, and Xingen Zhang. "Tripartite Motif Containing 11 Interacts with DUSP6 to Promote the Growth of Human Osteosarcoma Cells through Regulating ERK1/2 Pathway." BioMed Research International 2019 (December 26, 2019): 1–10. http://dx.doi.org/10.1155/2019/9612125.
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Tripartite Motif Containing 11 (TRIM11), an E3 ubiquitin ligase, is identified as a carcinogen causing certain human cancers. However, the specific role of TRIM11 is still uncovered in human osteosarcoma (OS) cells. To explore the role of TRIM11 in OS cells, TRIM11 was induced by silencing and overexpression in OS cells using RNA interference (RNAi) and lentiviral vector, respectively. qRT-PCR and western blot were used to examine the transcription and translation levels of the target gene. Cell count kit-8 (CCK-8) assays were established to analyze cell proliferation. Cell apoptosis ratio was determined via flow cytometry. In our analyses, TRIM11 was suggested to be upregulated, and it functioned as a pro-proliferation and antiapoptosis factor in OS cells. Moreover, the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 was used to examine the relationship between TRIM11 and ERK1/2 in OS cells. Results demonstrated that the role of TRIM11 was significantly disrupted by the ERK1/2 inhibitor PD98059. Interestingly, we found TRIM11 overexpression did not affect dual-specificity phosphatase 6 (DUSP6) transcription, but improved its translation in OS cells. Co-immunoprecipitation (Co-IP) analyses revealed that TRIM11 interacted with DUSP6. Importantly, overexpression of TRIM11 enhanced DUSP6 ubiquitination in OS cells. Therefore, TRIM11 might suppress the translation of DUSP6 via improving its ubiquitination. Additionally, TRIM11 silencing in OS cells significantly reduced its tumorigenicity in vivo. Overall, our findings firstly revealed that TRIM11 was an oncogene gene in the growth of OS cells and illustrated its potential function as a target in the treatment of OS.
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Zhou, Ling, Heng Wang, Min Zhong та ін. "The E3 Ubiquitin Ligase TRIM11 Facilitates Gastric Cancer Progression by Activating the Wnt/β-Catenin Pathway via Destabilizing Axin1 Protein". Journal of Oncology 2022 (21 лютого 2022): 1–14. http://dx.doi.org/10.1155/2022/8264059.
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Background. Aberrant expression of tripartite motif 11 (TRIM11) and the Wnt/β-catenin pathway are essential for facilitating tumorigenesis and progression in multiple types of cancer. Aim. To investigate the molecular changes linking the dysregulation of TRIM11 and Wnt/β-catenin pathway activation in gastric cancer (GC) progression. Methods. The expression levels of TRIM11 were detected in GC tissues and cells by immunohistochemistry and western blotting. The role of TRIM11 in the growth, proliferation, and invasion of gastric cancer cells was observed by a series of cell functional experiments and further verified in vivo. Co-immunoprecipitation (Co-IP), immunofluorescence, cycloheximide, and western blotting assays and other experiments were conducted to explore the mechanisms of TRIM11 underlying the regulation of the Wnt/β-catenin pathway. For further verification, rescue experiments were performed by cotransfection of TRIM11 and Axin1 siRNA in GC cells. Results. Using Co-IP assays, we identified TRIM11 as a potent binding partner of Axin1 in GC cells. Elevated TRIM11 levels were significantly correlated with unfavorable clinical outcomes and poor survival in patients with GC. In addition, TRIM11 promoted the cell proliferation and invasion capacities of GC cells in vitro and tumor growth in vivo. Mechanistic investigations revealed that TRIM11 destabilized Axin1 protein by interacting with Axin1, thus inducing the activation of the Wnt/β-catenin pathway. Moreover, we found that the oncogenic effects of TRIM11 on GC cells were partly mediated by suppression of Axin1. Furthermore, the protein expression of TRIM11 and Axin1 was negatively correlated in GC tissues. Conclusion. Collectively, our findings not only establish a pivotal TRIM11-Axin1-β-catenin axis in driving GC progression but also indicate that TRIM11 serves as a valuable therapeutic target for the treatment of GC patients.
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Wynne, Claire, Rowan Higgs, Christine Biron, and Caroline Jefferies. "The role of TRIM68 in Toll-like receptor and RIG-I-like receptor induced interferon production (72.5)." Journal of Immunology 188, no. 1_Supplement (2012): 72.5. http://dx.doi.org/10.4049/jimmunol.188.supp.72.5.
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Abstract Innate immune receptors such as Toll-like receptors (TLR) and RIG-I-like receptors (RLR) play key roles in viral recognition and interferon (IFN) production. Systemic Lupus Erythematosus (SLE) patients commonly present with an over production of type 1 IFNs which contribute to disease pathogenesis so understanding how to dampen down this response is of huge importance. The focus of this project is on the E3 ubiquitin ligase TRIM68, a known autoantigen in SLE. Results show TRIM68 to be a novel negative regulator of type 1 IFN production in both TLR- and RLR-dependent pathways. Proteomic analysis of TRIM68 containing complexes has allowed us to identify TRK-fused gene (TFG) as a TRIM68 target. The physiological role of TFG is still unknown but it has been shown to interact with NEMO and TANK, two proteins which modulate pro-inflammatory cytokine production. Thus the effects of TRIM68 on IFN production is via this novel regulation of TFG. To confirm the critical role of TRIM68 in IFN production we have knocked down TRIM68 in mice via injection of PLGA microparticles encapsulating shRNA against TRIM68 and studied the effects of TRIM68 knock down on viral-induced IFN production. TRIM68 knockdown mice display an increase in serum and peritoneum IFN levels post LCMV infection, indicating that TRIM68 is a key negative regulator of IFN production. This work carves the way for the development of novel therapeutics targeting TRIM68 for the treatment of IFN-driven disease such as SLE.
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Liu, Jinjin, Jun Rao, Xuming Lou, Jian Zhai, Zhenhua Ni, and Xiongbiao Wang. "Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53." Cellular Physiology and Biochemistry 44, no. 1 (2017): 255–66. http://dx.doi.org/10.1159/000484678.
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Background/Aims: The tripartite motif containing (TRIM) family plays crucial roles in tumor development and progression. However, little is known about the function and mechanism of TRIM11 in hepatocellular carcinoma (HCC). Methods: The expression levels of TRIM11 were examined by real-time PCR, Western blot and Immunohistochemical (IHC) staining. TRIM11 knockdown cells were produced by lentivirus infection, and functional assays, such as MTT, colony formation assay, migration and invasion assays and a xenograft tumor model were used to investigate the role of TRIM11 in HCC. We also determined the effect of TRIM11 on p53 signaling and its downstream molecules. Results: We found that TRIM11 mRNA and protein levels were significantly increased in HCC tissues as compared with normal tissues; increased levels correlated with poor patient survival. By loss- and gain-of-function investigations, knockdown of TRIM11 suppressed cell proliferation, migration, invasion in vitro and tumor growth in vivo. Moreover, TRIM11 negatively regulated p53 expression. Knockdown of p53 abrogated the in vitro and in vivo biological functions of TRIM11 shRNA in HCC cells. Conclusions: These data show that TRIM11 exerts its oncogenic effect in HCC by downregulating p53 both in vitro and in vivo. Our data provide new insights into the pathogenesis of HCC and indicate that TRIM11 may serve as a new therapeutic target for HCC treatment.
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Shang, Rongxin, Jiakuan Chen, Yang Gao, Jijun Chen, and Guoliang Han. "TRIM58 Interacts with ZEB1 to Suppress NSCLC Tumor Malignancy by Promoting ZEB1 Protein Degradation via UPP." Disease Markers 2023 (January 5, 2023): 1–13. http://dx.doi.org/10.1155/2023/5899662.
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Background. Currently, how to successfully control refractory and metastatic diseases remains a fundamental goal for clinicians to improve therapeutic effects for patients with non-small cell lung cancer (NSCLC). Several studies have discovered that TRIM58, a member of tripartite motif protein family, shows antitumor effect in multiple types of cancer. In this study, we aimed to further clarify the molecular regulatory network of TRIM58 and corresponding targets for NSCLC patients. Methods. TRIM58 expression in clinical tumor tissue samples and cancer cell lines was examined. Functional experiments including cellular invasion, cell metastasis, chemoresistance assay, and ubiquitination evaluation experiments were conducted to investigate the interaction between TRIM58 and ZEB1, which is a prime element of transcription factor network that controls epithelial-to-mesenchymal transition. Results. TRIM58 expression was characteristically decreased in NSCLC tumor tissues and cancer cell lines. Functional experiments demonstrated that TRIM58 suppression enhanced malignant biological behaviors including cellular survivability, migration, and invasion, as well as stem-like cellular phenotype of tumor cells. TRIM58 silencing also significantly enhanced the chemoresistance of NSCLC cells to chemoagents. TRIM58-ZEB1 interaction accelerated degradation of ZEB1 protein, thus further leading to the augment of tumor behaviors. Further detailed molecular experiments revealed that the interaction between TRIM58 and ZEB1 was mediated via ubiquitin-proteasome pathway (UPP). Conclusion. TRIM58 suppressed NSCLC through interacting with ZEB1 and promoting ZEB1 protein degradation via UPP. The present research sheds light on the interaction between TRIM58 and ZEB1, and TRIM58/ZEB1 axis might be the potential therapeutic targets of NSCLC.
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Ma, Xin, Sheng Zhang, Meiling Zhang, et al. "TRIM28 down-regulation on methylation imprints in bovine preimplantation embryos." Zygote 26, no. 6 (2018): 449–56. http://dx.doi.org/10.1017/s0967199418000424.
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SummaryTRIM28/KAP1/TIF1β was identified as a universal transcriptional co-repressor and is critical for regulating post-fertilization methylation reprogramming in preimplantation embryos. In this study, three siRNAs (si647, si742, and si1153) were designed to target the TRIM28 mRNA sequence. After transfection of the mixture of the three siRNA (siMix) into bovine fibroblast cells, the most effective one for TRIM28 knockdown was selected. By injecting RNAi directed against TRIM28 mRNA, we found that TRIM28 knockdown in oocytes had the most effect on the H19 gene, in which differentially methylated region (DMR) methylation was almost completely absent at the 2-cell stage (1.4%), while control embryos showed 74% methylation. In addition, global H3K9me3 levels at the 2-cell stage were significantly higher in the in vitro fertilization (IVF) group than in the TRIM28 knockdown group (P<0.05). We further show that TRIM28 is highly expressed during oocyte maturation and reaches peak levels at the 2-cell stage. In contrast, at this stage, TRIM28 expression in somatic cell nuclear transfer (SCNT) embryos decreased significantly (P<0.05), suggesting that Trim28 transcripts are lost during SCNT. TRIM28 is required for the maintenance of methylation imprints in bovine preimplantation embryos, and the loss of TRIM28 during SCNT may contribute to the unfaithful maintenance of imprints in cloned embryos.
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Li, Lin, Qi Li, Zhengrong Zou, Zoufang Huang та Yijian Chen. "TRIM10 Is Downregulated in Acute Myeloid Leukemia and Plays a Tumor Suppressive Role via Regulating NF-κB Pathway". Cancers 15, № 2 (2023): 417. http://dx.doi.org/10.3390/cancers15020417.
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Background: Accumulating evidence suggests that members of the tripartite motif (TRIMs) family play a crucial role in the development and progression of hematological malignancy. Here, we explored the expression and potential role of TRIM10 in acute myeloid leukemia (AML). Methods: The expression levels of TRIM10 were investigated in AML patients and cell lines by RNA-seq, qRT-PCR and Western blotting analysis. Lentiviral infection was used to regulate the level of TRIM10 in AML cells. The effects of TRIM10 on apoptosis, drug sensitivity and proliferation of AML cells were evaluated by flow cytometry and cell-counting kit-8 (CCK-8) assay, as well as being assessed in a murine model. Results: TRIM10 mRNA and protein expression was reduced in primary AML samples and AML cell lines in comparison to the normal controls and a human normal hematopoietic cell line, respectively. Moreover, overexpression of TRIM10 in HL60 and K562 cells inhibited AML cell proliferation and induced cell apoptosis. The nude mice study further confirmed that overexpression of TRIM10 blocked tumor growth and inhibited cell proliferation. In contrast, knockdown of TRIM10 in AML cells showed contrary results. Subsequent mechanistic studies demonstrated that knockdown of TRIM10 enhanced the expression of nuclear protein P65, which implied the activation of the NF-κB signal pathway. Consistently, overexpression of TRIM10 in AML cells showed a contrary result. These data indicated that inactivation of the NF-κB pathway is involved in TRIM10-mediated regulation in AML. TRIM10 expression can be de-repressed by a combination that targets both DNA methyltransferase and histone deacetylase. Conclusions: Our results strongly suggested that TRIM10 plays a tumor suppressive role in AML development associated with the NF-κB signal pathway and may be a potential target of epigenetic therapy against leukemia.
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Jin, Xin, Bin Zhang, Hao Zhang, and Haixin Yu. "Smoking-associated upregulation of CBX3 suppresses ARHGAP24 expression to activate Rac1 signaling and promote tumor progression in lung adenocarcinoma." Oncogene 41, no. 4 (2021): 538–49. http://dx.doi.org/10.1038/s41388-021-02114-8.
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AbstractAlthough tobacco smoking is a risk factor for lung adenocarcinoma (LUAD), the mechanisms by which tobacco smoking induces LUAD development remain elusive. Histone methylation levels in human bronchial epithelial cells have been reported to increase after exposure to cigarettes. In this study, we explored the mechanisms regulating histone methylation in LUAD in response to smoking. We found that the histone H3K9 methylation reader CBX3 was upregulated in current smokers with LUAD, and that CBX3 overexpression promoted LUAD progression. Functional enrichment analyses revealed that CBX3 regulated the activation of Rho GTPases in LUAD. We also found that by forming a complex with TRIM28, TRIM24, and RBBP4, CBX3 repressed the expression of ARHGAP24 and increased the amount of active Rac1 in LUAD cells. Collectively, these results suggest that smoking associated upregulation of CBX3 promotes LUAD progression by activating the ARHGAP24/Rac1 pathway. Hence, the CBX3/ARHGAP24/Rac1 axis may represent a promising therapeutic target in smoking-induced LUAD.
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Tan, Hongwei, Jin Qi, Guanghua Chu, and Zhaoyang Liu. "Tripartite Motif 16 Inhibits the Migration and Invasion in Ovarian Cancer Cells." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 25, no. 4 (2017): 551–58. http://dx.doi.org/10.3727/096504016x14758370595285.
Texte intégralRésumé :
Tripartite motif 16 (TRIM16), a member of the RING B-box coiled-coil (RBCC)/tripartite motif (TRIM) protein family, has been shown to play a role in tumor development and progression. However, the role of TRIM16 in ovarian cancer has never been revealed. Thus, in this study, we investigated the roles and mechanisms of TRIM16 in ovarian cancer. Our results demonstrated that TRIM16 expression was low in ovarian cancer cell lines. In addition, overexpression of TRIM16 significantly inhibited the migration and invasion in vitro, as well as suppressed the epithelial‐mesenchymal transition (EMT) phenotype in ovarian cancer cells. Furthermore, overexpression of TRIM16 greatly inhibited the protein expression levels of Shh, Smo, Ptc, Gli-1, MMP2, and MMP9 in ovarian cancer cells. Taken together, these results strongly suggest that TRIM16 inhibits the migration and invasion via suppressing the Sonic hedgehog signaling pathway in ovarian cancer cells. Thus, TRIM16 may be a novel potential therapeutic target for ovarian cancer.
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Han, Jiyu, Yanhong Wang, Haichao Zhou, Songtao Ai, and Daqian Wan. "Integrated Bioinformatics and Experimental Analysis Identified TRIM28 a Potential Prognostic Biomarker and Correlated with Immune Infiltrates in Liver Hepatocellular Carcinoma." Computational and Mathematical Methods in Medicine 2022 (October 4, 2022): 1–17. http://dx.doi.org/10.1155/2022/6267851.
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Background. Since the 1970s, liver hepatocellular carcinoma (LIHC) has experienced a constant rise in incidence and mortality rates, making the identification of LIHC biomarkers very important. Tripartite Motif-Containing 28 (TRIM28) is a protein-coding gene which encodes the tripartite motif-containing proteins (TRIMs) family and is associated with specific chromatin regions. TRIM28 expression and its prognostic value and impact on the immune system in LIHC patients are being investigated for the first time. Methods. The TRIM28 expression data from TCGA database was used to analyze TRIM28 expression, clinicopathological information, gene enrichment, and immune infiltration and conduct additional bioinformatics analysis. R language was used for statistical analysis. TIMER, CIBERSORT, and ssGSEA were used to assess immune responses of TRIM28 in LIHC. Next, the results were validated using GEPIA, ROC analysis, and immunohistochemical staining pictures from the THPA. GSE14520, GSE63898, and GSE87630 datasets were analyzed using ROC analysis to further evaluate TRIM28’s diagnostic value. To ultimately determine TRIM28 expression, we performed qRT-PCR (quantitative real-time polymerase chain reaction). Results. High TRIM28 expression level was associated with T classification, pathologic stage, histologic grade, and serum AFP levels. In patients with LIHC, TRIM28 was an independent risk factor for a poor prognosis. The pathways ligand-receptor interaction, which is critical in LIHC patients, were closely associated with TRIM28 expression, and the function of DC could be suppressed by overexpression of TRIM28. As a final step, our results were validated by GEO data and qRT-PCR. Conclusions. TRIM28 will shed new light on LIHC mechanisms. As an effective diagnostic and intervention tool, this gene will be able to diagnose and treat LIHC at an early stage.
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Yuan, Peng, Yiyi Zhou, Rui Wang, et al. "TRIM58 Interacts with Pyruvate Kinase M2 to Inhibit Tumorigenicity in Human Osteosarcoma Cells." BioMed Research International 2020 (March 7, 2020): 1–9. http://dx.doi.org/10.1155/2020/8450606.
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Background. Tripartite motif containing 58 (TRIM58), an E3 ubiquitin ligase, is reported as a suppressor gene in certain human tumors. However, the biological function of TRIM58 in osteosarcoma (OS) is still less identified. Methods. In the present study, TRIM58 induced silencing and overexpression in OS cells using RNA interference (RNAi) and lentiviral-mediated vector, respectively. Cell proliferation profiles were analyzed using cell counting kit-8 (CCK-8) assay. Cell apoptosis profiles were determined using a flow cytometer. qRT-PCR and western blot were used to determine gene expression. Coimmunoprecipitation (Co-IP) assay was used to examine protein interaction. Results. Our results demonstrated TRIM58 was downregulated in human OS tissues. Overexpression of TRIM58 remarkably suppressed the growth of OS cells and decreased glucose transportation and lactate secretion. These results indicated that TRIM58 involved in the regulation of energy metabolism in OS cells. Importantly, TRIM58 interacted with pyruvate kinase M2 (PKM2) in OS cells. Moreover, TRIM58 might inhibit the activity of PKM2 through enhancing its polyubiquitination in OS cells. Conclusions. This analysis not only explored a deep understanding of the biological function of TRIM58 but also indicated its signaling pathway in OS cells.
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Chang, Yao-Jen, Zhifu Kang, Jiayuan Bei, et al. "Generation of TRIM28 Knockout K562 Cells by CRISPR/Cas9 Genome Editing and Characterization of TRIM28-Regulated Gene Expression in Cell Proliferation and Hemoglobin Beta Subunits." International Journal of Molecular Sciences 23, no. 12 (2022): 6839. http://dx.doi.org/10.3390/ijms23126839.
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TRIM28 is a scaffold protein that interacts with DNA-binding proteins and recruits corepressor complexes to cause gene silencing. TRIM28 contributes to physiological functions such as cell growth and differentiation. In the chronic myeloid leukemia cell line K562, we edited TRIM28 using CRISPR/Cas9 technology, and the complete and partial knockout (KO) cell clones were obtained and confirmed using quantitative droplet digital PCR (ddPCR) technology. The amplicon sequencing demonstrated no off-target effects in our gene editing experiments. The TRIM28 KO cells grew slowly and appeared red, seeming to have a tendency towards erythroid differentiation. To understand how TRIM28 controls K562 cell proliferation and differentiation, transcriptome profiling analysis was performed in wild-type and KO cells to identify TRIM28-regulated genes. Some of the RNAs that encode the proteins regulating the cell cycle were increased (such as p21) or decreased (such as cyclin D2) in TRIM28 KO cell clones; a tumor marker, the MAGE (melanoma antigen) family, which is involved in cell proliferation was reduced. Moreover, we found that knockout of TRIM28 can induce miR-874 expression to downregulate MAGEC2 mRNA via post-transcriptional regulation. The embryonic epsilon-globin gene was significantly increased in TRIM28 KO cell clones through the downregulation of transcription repressor SOX6. Taken together, we provide evidence to demonstrate the regulatory network of TRIM28-mediated cell growth and erythroid differentiation in K562 leukemia cells.
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Neo, Shu Hui, Yoko Itahana, Jennifer Alagu, et al. "TRIM28 Is an E3 Ligase for ARF-Mediated NPM1/B23 SUMOylation That Represses Centrosome Amplification." Molecular and Cellular Biology 35, no. 16 (2015): 2851–63. http://dx.doi.org/10.1128/mcb.01064-14.
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The tumor suppressor ARF enhances the SUMOylation of target proteins; however, the physiological function of ARF-mediated SUMOylation has been unclear due to the lack of a known, associated E3 SUMO ligase. Here we uncover TRIM28/KAP1 as a novel ARF-binding protein and SUMO E3 ligase for NPM1/B23. ARF and TRIM28 cooperate to SUMOylate NPM1, a nucleolar protein that regulates centrosome duplication and genomic stability. ARF-mediated SUMOylation of NPM1 was attenuated by TRIM28 depletion and enhanced by TRIM28 overexpression. Coexpression of ARF and TRIM28 promoted NPM1 centrosomal localization by enhancing its SUMOylation and suppressed centrosome amplification; these functions required the E3 ligase activity of TRIM28. Conversely, depletion of ARF or TRIM28 increased centrosome amplification. ARF also counteracted oncogenic Ras-induced centrosome amplification. Centrosome amplification is often induced by oncogenic insults, leading to genomic instability. However, the mechanisms employed by tumor suppressors to protect the genome are poorly understood. Our findings suggest a novel role for ARF in maintaining genome integrity by facilitating TRIM28-mediated SUMOylation of NPM1, thus preventing centrosome amplification.
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Di, Kaijun, Daniela Abrams, Pratik Yadav, Bhaskar Das, and Daniela Bota. "EXTH-50. IDENTIFYING TRIM11 AS A POTENTIAL THERAPEUTIC TARGET FOR MALIGNANT GLIOMAS." Neuro-Oncology 24, Supplement_7 (2022): vii220. http://dx.doi.org/10.1093/neuonc/noac209.848.
Texte intégralRésumé :
Abstract TRIM11 (tripartite motif-containing protein 11) belongs to the TRIM/RBCC (the RING B-box coiled-coil) family of E3 ubiquitin ligases. Members of this family have been implicated in development, neurodegenerative diseases, cellular response to viral infection and cancer. Glioblastoma (GBM) is an aggressive infiltrative brain tumor with poor prognosis. Our previous work demonstrated that TRIM11 is over-expressed in high-grade gliomas and promotes proliferation, invasion, migration and tumor growth, suggesting TRIM11 is a target for malignant glioma treatment. Here we reported the effect of TRIM11 on GBM progression in vivo using immunocompromised mice intracranially implanted with GBM xenografts over-expressing TRIM11. The control group mice survived longer than the mice bearing TRIM11 over-expressing xenografts (P&lt; 0.5), suggesting TRIM11 enhances tumor progression in vivo. The oncogenic effect of TRIM11 may be related to its influence on apoptosis pathway as a robust induction of poly (ADP-ribose) polymerase (PARP) was observed in TRIM11 over-expressing GBM cells. PARP could repair DNA damage caused by UV light, radiation, and certain anticancer drugs, etc. Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for GBM through alkylating/methylating DNA, leading to DNA damage and death of tumor cells. TRIM11 over-expressing GBM cells were found more resistant to TMZ and showed a higher survival rate compared to parental cells, indicating that TRIM11 might be a therapeutic target for GBM. Based on homology modeling we designed and synthesized small library of TRIM11 inhibitors, and identified one compound (BT# 592) significantly inhibited the growth of GBM cells in a dose-dependent manner, implicating that TRIM11 inhibitors may serve as novel agents for malignant glioma treatment. We are in the process to develop more active compounds using SAR studies to identify hit-to-lead compounds as potential therapeutics for GBM.
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Lu, Zhengri, Mengen Deng, Genshan Ma та Lijuan Chen. "TRIM38 protects H9c2 cells from hypoxia/reoxygenation injury via the TRAF6/TAK1/NF-κB signalling pathway". PeerJ 10 (29 серпня 2022): e13815. http://dx.doi.org/10.7717/peerj.13815.
Texte intégralRésumé :
Tripartite motif (TRIM) 38 is a ubiquitin E3 protein ligase that is involved in various intracellular physiological processes. However, the role of TRIM38 in myocardial ischaemia/reperfusion (I/R) injury remains to be elucidated. We aimed to establish an in vitro cellular hypoxia/reperfusion (H/R) model to explore the role and potential mechanisms of TRIM38 in H9c2, a rat cardiomyoblast cell line. Recombinant adenoviruses for silencing or overexpressing TRIM38 were constructed and transfected into H9c2 cells. Western blotanalysisshowed that TRIM38 expression was significantly decreased after H/R injury. Functionally, TRIM38 expression relieved inflammatory responses and oxidative stress, and inhibited H/R-induced apoptosis in H9c2 cells. Mechanistically, TRIM38 overexpression inhibited H/R-induced transforming growth factor beta-activated kinase 1 (TAK1)/nuclear factor-kappa B (NF-κB) pathway activity in H9c2 cells. The opposite results were observed after TRIM38 knockdown. Furthermore, H/R-induced injury aggravated by TRIM38 deficiency in H9c2 cells was reversed upon treatment with 5Z-7-oxozeaenol, a TAK1 inhibitor. Therefore, TRIM38 reduction attenuated the anti-apoptotic capacity and anti-inflammatory potential of H/R-stimulated H9c2 cells by activating the TAK1/NF-κB signalling pathway. Specifically, TRIM38 alleviated H/R-induced H9c2 cell injury by promoting TNF receptor-associated factor 6 degradation, which led to the inactivation of the TAK1/NF-κB signalling pathway. Thus, our study provides new insights into the molecular mechanisms underlying H/R-induced myocardial injuries.
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Dang, Xiaoyan, Yong Qin, Changwei Gu, Jiangli Sun, Rui Zhang, and Zhuo Peng. "Knockdown of Tripartite Motif 8 Protects H9C2 Cells Against Hypoxia/Reoxygenation-Induced Injury Through the Activation of PI3K/Akt Signaling Pathway." Cell Transplantation 29 (January 1, 2020): 096368972094924. http://dx.doi.org/10.1177/0963689720949247.
Texte intégralRésumé :
Tripartite motif 8 (TRIM8) is a member of the TRIM protein family that has been found to be implicated in cardiovascular disease. However, the role of TRIM8 in myocardial ischemia/reperfusion (I/R) has not been investigated. We aimed to explore the effect of TRIM8 on cardiomyocyte H9c2 cells exposed to hypoxia/reoxygenation (H/R). We found that TRIM8 expression was markedly upregulated in H9c2 cells after stimulation with H/R. Gain- and loss-of-function assays proved that TRIM8 knockdown improved cell viability of H/R-stimulated H9c2 cells. In addition, TRIM8 knockdown suppressed reactive oxygen species production and elevated the levels of superoxide dismutase and glutathione peroxidase. Knockdown of TRIM8 suppressed the caspase-3 activity, as well as caused significant increase in bcl-2 expression and decrease in bax expression. Furthermore, TRIM8 overexpression exhibited apposite effects with knockdown of TRIM8. Finally, knockdown of TRIM8 enhanced the activation of PI3K/Akt signaling pathway in H/R-stimulated H9c2 cells. Inhibition of PI3K/Akt by LY294002 reversed the effects of TRIM8 knockdown on cell viability, oxidative stress, and apoptosis of H9c2 cells. These present findings defined TRIM8 as a therapeutic target for attenuating and preventing myocardial I/R injury.
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Li, Min, Xiaohua Xu, Chou-Wei Chang, and Yilun Liu. "TRIM28 functions as the SUMO E3 ligase for PCNA in prevention of transcription induced DNA breaks." Proceedings of the National Academy of Sciences 117, no. 38 (2020): 23588–96. http://dx.doi.org/10.1073/pnas.2004122117.
Texte intégralRésumé :
In human cells, the DNA replication factor proliferating cell nuclear antigen (PCNA) can be conjugated to either the small ubiquitinlike modifier SUMO1 or SUMO2, but only SUMO2-conjugated PCNA is induced by transcription to facilitate resolution of transcription–replication conflict (TRC). To date, the SUMO E3 ligase that provides substrate specificity for SUMO2-PCNA conjugation in response to TRC remains unknown. Using a proteomic approach, we identified TRIM28 as the E3 ligase that catalyzes SUMO2-PCNA conjugation. In vitro, TRIM28, together with the RNA polymerase II (RNAPII)-interacting protein RECQ5, promotes SUMO2-PCNA conjugation but inhibits SUMO1-PCNA formation. This activity requires a PCNA-interacting protein (PIP) motif located within the bromodomain of TRIM28. In cells, TRIM28 interaction with PCNA on human chromatin is dependent on both transcription and RECQ5, and SUMO2-PCNA level correlates with TRIM28 expression. As a consequence, TRIM28 depletion led to RNAPII accumulation at TRC sites, and expression of a TRIM28 PIP mutant failed to suppress TRC-induced DNA breaks.
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Huang, Xuan, Yong Li, Xiuzhen Li, Daping Fan, Hong-Bo Xin та Mingui Fu. "TRIM14 promotes endothelial activation via activating NF-κB signaling pathway". Journal of Molecular Cell Biology 12, № 3 (2019): 176–89. http://dx.doi.org/10.1093/jmcb/mjz040.
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AbstractEndothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases; however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-κB signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-α, IL-1β, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-α in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-α stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of IκBα and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14–NF-κB forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.
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Narayan, Kavitha, та Joonsoo Kang. "The RING E3 ubiquitin ligase Trim13 (Rfp2) influences αβ and γδ T cell development (B5)". Journal of Immunology 178, № 1_Supplement (2007): LB1. http://dx.doi.org/10.4049/jimmunol.178.supp.b5.
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Abstract αβ and γδ T cells arise from a common precursor in the thymus, but the mechanisms involved in this lineage specification remain poorly defined. We identified Tripartite Motif 13 (Trim13) as a γδ lineage biased gene. TRIM13, an RBCC protein, is an ER/nuclear membrane localized RING E3 ubiquitin ligase involved the ER-associated degradation pathway. Similar to other γδ lineage biased genes, the expression of Trim13 in γδ T cells is regulated in part by trans priming signals from αβ lineage DP thymocytes, and Trim13 is also expressed in some unconventional αβ lineage subsets. Interestingly, Trim13 is only expressed in about half of γδ thymocytes, suggesting that Trim13 may mark a subset of γδ T cells distinguishable by different thymic selection requirements, different stages of maturity, and/or functional competence. Preliminary results indicate that ectopic Trim13 expression is detrimental to αβ T cell development, but is conducive for enhanced γδ T cell generation and B cell development and/or expansion. These results suggest that Trim13 may play a role in T and B cell development, and that its expression may segregate specific subsets of T cells. Given its role as a nuclear membrane E3 ubiquitin ligase, it is possible that TRIM13 functions, in part, by controlling the relative abundance of transcription factors involved in lineage differentiation or maturation, resulting in different developmental outcomes.
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Liu, Ruoxi, Hao Wu та Huanjin Song. "Knockdown of TRIM8 Attenuates IL-1β-induced Inflammatory Response in Osteoarthritis Chondrocytes Through the Inactivation of NF-κB Pathway". Cell Transplantation 29 (1 січня 2020): 096368972094360. http://dx.doi.org/10.1177/0963689720943604.
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Osteoarthritis (OA) is a degenerative joint disease associated with inflammatory response. Tripartite motif 8 (TRIM8) is a member of TRIM family that has been found to regulate inflammation. The present study was aimed to evaluate the role of TRIM8 in OA chondrocytes. Our results showed that TRIM8 expression was significantly increased in interleukin 1 beta (IL-1β)-stimulated OA chondrocytes. To knock down the TRIM8 expression in chondrocytes, the chondrocytes were transfected with si-TRIM8. Knockdown of TRIM8 attenuated IL-1β-induced production of inflammatory mediators including nitric oxide and prostaglandin E2. The increased expression levels of inducible nitric oxide synthase and cyclooxygenase-2 in IL-1β-induced chondrocytes were suppressed by TRIM8 knockdown. The IL-1β-induced production of proinflammatory cytokines including TNF-α and IL-6 was significantly decreased after transfection with si-TRIM8. Besides, knockdown of TRIM8 mitigated the IL-1β-induced decrease in aggrecan and collagen-II proteins expression and increase in matrix-degrading enzymes in chondrocytes. Furthermore, TRIM8 knockdown prevented IL-1β-induced nuclear factor kappa B (NF-κB) activation in chondrocytes. Taken together, these findings indicated that knockdown of TRIM8 attenuates IL-1β-induced inflammatory response in OA chondrocytes through the inactivation of NF-κB pathway. Thus, targeting TRIM8 might provide therapeutic treatment for OA.
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Li, Yong, Daping Fan та Mingui Fu. "TRIM14 promotes endothelial activation via NF-κB signaling pathway". Journal of Immunology 202, № 1_Supplement (2019): 59.9. http://dx.doi.org/10.4049/jimmunol.202.supp.59.9.
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Abstract Endothelial activation induced by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases, however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we report that TRIM14 promotes endothelial activation by enhancing cytokine-induced NF-κB activation. TRIM14 is highly expressed in human vascular endothelial cells, and markedly induced by TNF-α, IL-1β and LPS in both HUVECs and aortas of LPS-injected mice. Overexpression of TRIM14 significantly increased TNF-induced expression of adhesion molecules such as VCAM-1, ICAM-1, E-Selectin and cytokines in human endothelial cells, and by which it facilitated monocyte adhesion to the activated endothelial cells. Conversely, its silencing has opposite effect on endothelial activation. We further found that TRIM14 interacted with TAK1 and NEMO to facilitate the IKK complex formation and enhanced cytokine-induced phosphorylation of IκBα and NF-κB nuclear translocation. Moreover, we found that TRIM14 underwent K63-linked ubiquitination during TNF-induced endothelial activation, which is required for its positive role in the regulation of NF-κB signaling and endothelial inflammation. Meanwhile, NF-κB can directly bind to the promoter regions of TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein levels were significantly up-regulated in mouse and human atheroma compared to normal arteries. Taken together, the current study demonstrates the new role of TRIM14 in the regulation of endothelial activation and suggests that TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.
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Thom, Christopher S., Eugene Khandros, Yu Yao, et al. "Trim58 Is a Putative E3 Ubiquitin Ligase That Functions in Late Stage Erythropoiesis." Blood 120, no. 21 (2012): 83. http://dx.doi.org/10.1182/blood.v120.21.83.83.
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Abstract Abstract 83 Protein quality control (PQC) pathways, including the ubiquitin-proteasome system, play critical roles in tissue development, including erythropoiesis. PQC mechanisms also regulate mitosis by facilitating the degradation of cell cycle stage-specific proteins. During erythropoiesis, committed progenitors undergo specialized cell divisions that facilitate terminal maturation and culminate in nuclear extrusion. We identified the tri partite motif-containing protein family member Trim58 as a putative ubiquitin ligase that is specifically expressed during late erythroid maturation as cells undergo their final round of division. Genome-wide ChIP-Seq and transcriptome analyses indicate that the Trim58 gene is activated by the essential erythroid nuclear proteins GATA1 and SCL/TAL1 (Cheng et al. Genome Research 2009). In human genome-wide association studies (GWAS), TRIM58 gene polymorphisms correlate with altered erythrocyte size (Ganesh et al. Nature Genetics 2009; Kamatani et al. Nature Genetics 2010). To study the function of Trim58, we used shRNAs to inhibit its expression in primary erythroid cultures of murine fetal liver hematopoietic progenitors. Four Trim58 shRNAs knocked down mRNA and protein expression from 60–90%. Compared to controls, Trim58 knockdown had no effect on erythroblast proliferation, survival, hemoglobinization, or expression of the maturation markers Ter119 and CD44. However, Trim58-deficient erythroblasts exhibited defective enucleation to the reticulocyte stage after 48 hours in culture (54% reticulocytes vs. 69% in controls, p<0.05, n= 4 replicates) (Figure 1). Additionally, Trim58 knockdown caused late-stage erythroblasts to acquire 2 or more nuclei (15.1% vs. 1.7% in controls, p<0.01, n= 3 experiments). Similar results were observed using 4 different Trim58 shRNAs compared to 3 controls (mock infection, scrambled shRNA, or anti-luciferase shRNA). Immunofluorescence showed that endogenous Trim58 or ectopically expressed mCherry-Trim58 fusion protein both localized to mitotic structures including centrosomes, which participate in chromosomal organization during metaphase, and the midbody, which connects dividing cells in late telophase. Immunoprecipitation-mass spectrometry and GST-pulldown studies demonstrated that Trim58 interacts with dynein and Nup153, two proteins that are known to participate in cell division. Based on these findings, we hypothesize that Trim58 is an E3 ubiquitin ligase that regulates terminal erythroid cell cycles and enucleation by coordinating nuclear division (karyokinesis) with cytokinesis. Our findings provide new insights into mechanisms of normal erythropoiesis and are relevant to the pathophysiology of numerous disorders associated with erythroid precursor multinuclearity, including myelodysplastic syndrome and the congenital dyserythropoietic anemias. Figure 1. Compared to control shRNA treatment (shLuciferase), Trim58 knockdown (shTrim58) in differentiating primary murine erythroblasts causes a late maturation block with reduced reticulocytes and accumulation of multinuclear erythroblasts. Figure 1. Compared to control shRNA treatment (shLuciferase), Trim58 knockdown (shTrim58) in differentiating primary murine erythroblasts causes a late maturation block with reduced reticulocytes and accumulation of multinuclear erythroblasts. Disclosures: No relevant conflicts of interest to declare.
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Czerwinska, Patrycja, Anna Maria Jaworska, Nikola Agata Wlodarczyk, and Andrzej Adam Mackiewicz. "Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein." Cancers 12, no. 10 (2020): 2998. http://dx.doi.org/10.3390/cancers12102998.
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TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition.
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Tomonori, Hosoya, Mary Clifford, and James Engel. "TRIM28 Is Essential For Erythroblast Differentiation In The Mouse." Blood 122, no. 21 (2013): 2182. http://dx.doi.org/10.1182/blood.v122.21.2182.2182.
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Abstract We previously identified TRIM28 (TIF1β, KAP-1) as a component of the mammalian DRED complex that prior studies had implicated as an embryonic/fetal β-type globin gene repressor. TRIM28 has been previously characterized as a transcriptional co-repressor thst interacts with heterochromatin protein 1 (HP1) and histone H3K9 methyltransferase SETDB1. We tested the contribution of TRIM28 to globin gene regulation and erythropoiesis by employing a mutant mouse that could be inducibly ablated for the Trim28 gene during the adult stage. The Mx1Cre transgene was activated by injecting poly(I:C) 5 times into these compound mutant mice every 48 hours. We hypothesized that TRIM28 might normally contribute to silencing of the embryonic and/or fetal globin genes and therefore that one might anticipate that the mouse εY- and/or βH1-globin genes (the structural homologues of human embryonic ε− and fetal γ-globin genes, respectively) would be de-repressed in the absence of TRIM28. To our surprise, the expression of εY- and βH1-globin mRNAs was not altered after induced genetic loss of Trim28. However, we discovered that its loss results in defective immature erythropoiesis in bone marrow and consequently to normocytic anemia. To address possible mechanisms that might be responsible for this observed defect in erythropoiesis, we analyzed staged, immature erythroid cells isolated from the Trim28 mutant mice by RNA-Seq and qRT-PCR. We observed diminished expression of multiple erythroid transcription factors and heme biosynthetic enzymes in the mutant. We also discovered increased expression of multiple apoptosis-related genes, and experimentally confirmed an increase in early apoptotic cells (Annexin V+ DAPI-) in the Trim28 mutant erythroblasts. We conclude that TRIM28 is vital for immature erythropoiesis in the adult bone marrow. Disclosures: No relevant conflicts of interest to declare.
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Baek, Suk-Hwan, Bin Huang та Han Zhong Pei. "Role of Trim13 in toll-like receptor 2-mediated NF-κB activation". Journal of Immunology 198, № 1_Supplement (2017): 75.10. http://dx.doi.org/10.4049/jimmunol.198.supp.75.10.
Texte intégralRésumé :
Abstract NF-κB regulates the expression of a various genes involved in diverse cellular processes including inflammation and immunity. Ubiquitination is a versatile post-translational modification involved in NF-κB activation of toll-like receptor (TLR) signaling. Here, we demonstrated that Trim13, an E3 ubiquitin ligase, is up-regulated in macrophages upon stimulation with TLR2 ligand. Knock-down of Trim13 attenuated TLR2-mediated production of cytokines/chemokines and formation of foam cells, as well as activation of NF-κB. Trim13 interacts with TRAF6 and potentiates NF-κB activity via ubiquitination of TRAF6. Overexpression of inactive mutant (C10/13A) or RING deletion mutant of Trim13 did not potentiate ubiquitination of TRAF6 or activation of NF-κB. These results suggest that the effects of Trim13 are dependent on its E3 ligase activity. Trim13 used K29-linked polyubiquitin chains for TRAF6 ubiquitination to promote NF-κB activity and thus potentiated activation of TLR2-mediated immune responses. Our data identify Trim13 as a positive regulator of NF-κB activation and suggest that K29-linked polyubiquitination is a specific ubiquitin-linked pattern involved in the control of TLR2 signaling.
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Liu, Yanwei, Yifan Wei, Ziwei Zhou, et al. "Overexpression of TRIM16 Reduces the Titer of H5N1 Highly Pathogenic Avian Influenza Virus and Promotes the Expression of Antioxidant Genes through Regulating the SQSTM1-NRF2-KEAP1 Axis." Viruses 15, no. 2 (2023): 391. http://dx.doi.org/10.3390/v15020391.
Texte intégralRésumé :
Oxidative stress plays a vital role in viral replication. Tripartite motif containing 16 (TRIM16) is involved in diverse cellular processes. However, the role of TRIM16 in oxidative stress induced by infection of the highly pathogenic H5N1 avian influenza virus (HPAIV) is unclear. We found that under conditions of H5N1 HPAIV infection, reactive oxygen species (ROS) levels in A549 cells peaked at 24 h post infection (hpi), and antioxidant genes’ expression levels were down-regulated. Overexpression of TRIM16 in A549 cells resulted in a decrease in the titter of H5N1 HPAIV and led to significant up-regulation of the antioxidant genes’ expression levels, which indicates that TRIM16 positively regulates the sequestosome 1/Kelch-like associated enoyl-CoA hydratase 1 protein/nuclear factor erythrocyte 2-derived 2-like 2 (SQSTM1/NRF2/KEAP1) pathway. Under basal conditions, TRIM16 led to a modification of NRF2 through an increase in K63-linked poly-ubiquitination of NRF2. Collectively, our findings provide new insight into understanding TRIM16′s role in anti-oxidative stress in H5N1 HPAIV infected A549 cells.
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Wang, Yinfang, Yilong Hao, Yuanyuan Zhao та ін. "TRIM28 and TRIM27 are required for expressions of PDGFRβ and contractile phenotypic genes by vascular smooth muscle cells". FASEB Journal 34, № 5 (2020): 6271–83. http://dx.doi.org/10.1096/fj.201902828rr.
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Forlani, Greta, Filippo Turrini, Guido Poli, Elisa Vicenzi, and Roberto Accolla. "P-D2 TRIM22 binds to CIITA and sequesters it into nuclear bodies containing TRIM19/PML and Cyclin T1." JAIDS Journal of Acquired Immune Deficiency Syndromes 77 (April 2018): 59. http://dx.doi.org/10.1097/01.qai.0000532512.60222.b5.
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