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1
Ci, Yali, and Lei Shi. "Compartmentalized replication organelle of flavivirus at the ER and the factors involved." Cellular and Molecular Life Sciences 78, no. 11 (April 12, 2021): 4939–54. http://dx.doi.org/10.1007/s00018-021-03834-6.
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AbstractFlaviviruses are positive-sense single-stranded RNA viruses that pose a considerable threat to human health. Flaviviruses replicate in compartmentalized replication organelles derived from the host endoplasmic reticulum (ER). The characteristic architecture of flavivirus replication organelles includes invaginated vesicle packets and convoluted membrane structures. Multiple factors, including both viral proteins and host factors, contribute to the biogenesis of the flavivirus replication organelle. Several viral nonstructural (NS) proteins with membrane activity induce ER rearrangement to build replication compartments, and other NS proteins constitute the replication complexes (RC) in the compartments. Host protein and lipid factors facilitate the formation of replication organelles. The lipid membrane, proteins and viral RNA together form the functional compartmentalized replication organelle, in which the flaviviruses efficiently synthesize viral RNA. Here, we reviewed recent advances in understanding the structure and biogenesis of flavivirus replication organelles, and we further discuss the function of virus NS proteins and related host factors as well as their roles in building the replication organelle.
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Lin, Wenwu, Zhike Feng, K. Reddisiva Prasanth, Yuyan Liu, and Peter D. Nagy. "Dynamic interplay between the co-opted Fis1 mitochondrial fission protein and membrane contact site proteins in supporting tombusvirus replication." PLOS Pathogens 17, no. 3 (March 16, 2021): e1009423. http://dx.doi.org/10.1371/journal.ppat.1009423.
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Plus-stranded RNA viruses have limited coding capacity and have to co-opt numerous pro-viral host factors to support their replication. Many of the co-opted host factors support the biogenesis of the viral replication compartments and the formation of viral replicase complexes on subverted subcellular membrane surfaces. Tomato bushy stunt virus (TBSV) exploits peroxisomal membranes, whereas the closely-related carnation Italian ringspot virus (CIRV) hijacks the outer membranes of mitochondria. How these organellar membranes can be recruited into pro-viral roles is not completely understood. Here, we show that the highly conserved Fis1 mitochondrial fission protein is co-opted by both TBSV and CIRV via direct interactions with the p33/p36 replication proteins. Deletion ofFIS1in yeast or knockdown of the homologous Fis1 in plants inhibits tombusvirus replication. Instead of the canonical function in mitochondrial fission and peroxisome division, the tethering function of Fis1 is exploited by tombusviruses to facilitate the subversion of membrane contact site (MCS) proteins and peroxisomal/mitochondrial membranes for the biogenesis of the replication compartment. We propose that the dynamic interactions of Fis1 with MCS proteins, such as the ER resident VAP tethering proteins, Sac1 PI4P phosphatase and the cytosolic OSBP-like oxysterol-binding proteins, promote the formation and facilitate the stabilization of virus-induced vMCSs, which enrich sterols within the replication compartment. We show that this novel function of Fis1 is exploited by tombusviruses to build nuclease-insensitive viral replication compartment.
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Nagy, Peter D. "Exploitation of Host Factors and Cellular Pathways by Tombusviruses for the Biogenesis of the Viral Replication Organelles." Proceedings 50, no. 1 (June 4, 2020): 18. http://dx.doi.org/10.3390/proceedings2020050018.
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Plus-stranded RNA viruses recruit cellular vesicles and co-opt cellular proteins involved in cellular metabolism and lipid biosynthesis to build viral replicase complexes (VRCs) within the large viral replication compartments. We use tombusviruses (TBSV), which are small (+)RNA viruses, as model plant viruses to study virus replication, recombination, and virus–host interactions using yeast (Saccharomyces cerevisiae) as a surrogate host. Several systematic genome-wide screens and global proteomic and lipidomic approaches have led to the identification of ~500 host proteins/genes that are implicated in TBSV replication. We characterized the role of two-dozen co-opted host proteins, sterols, and phosphatidylethanolamine in tombusvirus VRC assembly and viral RNA synthesis. We provide evidence on the critical roles of phosphoinositides and co-opted membrane-shaping proteins in VRC formation. We also present data that tombusviruses hijack the glycolytic and fermentation pathways to obtain ATP, which is required for the biogenesis of the replication compartment. Finally, we show evidence that TBSV usurps COPII and endosomal vesicles to form a unique microenvironment involving peroxisomes and endoplasmic reticulum (ER) to support viral replication. These new insights highlight the amazingly complex nature of virus-host interactions.
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Ortiz, Cristina Risco. "Imaging Viral Factories." Proceedings 50, no. 1 (June 1, 2020): 3. http://dx.doi.org/10.3390/proceedings2020050003.
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Viruses remodel cellular compartments to build their replication factories. Remarkably, viruses are also able to induce new membranes and new organelles. As a result of recent advances in light and transmission electron microscopy (TEM), we are starting to become aware of the variety of structures that viruses assemble inside cells. Viral factories are intracellular compartments harboring replication organelles that contain viral replication complexes and the sites of virus particle assembly. This lecture will revise the most relevant imaging technologies for studying the biogenesis of viral replication factories. Live cell microscopy, correlative light and electron microscopy, cryo-TEM, and three-dimensional imaging methods are unveiling how viruses manipulate cell organization. In particular, methods for molecular mapping in situ, in two and three dimensions, are revealing how macromolecular complexes build functional replication complexes inside infected cells. The combination of all these imaging approaches is uncovering the viral lifecycle events with a detail never seen before.
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Reuter, Tatjana, Stephanie Vorwerk, Viktoria Liss, Tzu-Chiao Chao, Michael Hensel, and Nicole Hansmeier. "Proteomic Analysis of Salmonella-modified Membranes Reveals Adaptations to Macrophage Hosts." Molecular & Cellular Proteomics 19, no. 5 (February 26, 2020): 900–912. http://dx.doi.org/10.1074/mcp.ra119.001841.
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Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.
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Arakawa, Masashi, and Eiji Morita. "Flavivirus Replication Organelle Biogenesis in the Endoplasmic Reticulum: Comparison with Other Single-Stranded Positive-Sense RNA Viruses." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2336. http://dx.doi.org/10.3390/ijms20092336.
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Some single-stranded positive-sense RNA [ssRNA(+)] viruses, including Flavivirus, generate specific organelle-like structures in the host endoplasmic reticulum (ER). These structures are called virus replication organelles and consist of two distinct subdomains, the vesicle packets (VPs) and the convoluted membranes (CMs). The VPs are clusters of small vesicle compartments and are considered to be the site of viral genome replication. The CMs are electron-dense amorphous structures observed in proximity to the VPs, but the exact roles of CMs are mostly unknown. Several recent studies have revealed that flaviviruses recruit several host factors that are usually used for the biogenesis of other conventional organelles and usurp their function to generate virus replication organelles. In the current review, we summarize recent studies focusing on the role of host factors in the formation of virus replication organelles and discuss how these intricate membrane structures are organized.
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Dolnik, Olga, Gesche K. Gerresheim, and Nadine Biedenkopf. "New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections." Cells 10, no. 6 (June 10, 2021): 1460. http://dx.doi.org/10.3390/cells10061460.
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Infections by negative strand RNA viruses (NSVs) induce the formation of viral inclusion bodies (IBs) in the host cell that segregate viral as well as cellular proteins to enable efficient viral replication. The induction of those membrane-less viral compartments leads inevitably to structural remodeling of the cellular architecture. Recent studies suggested that viral IBs have properties of biomolecular condensates (or liquid organelles), as have previously been shown for other membrane-less cellular compartments like stress granules or P-bodies. Biomolecular condensates are highly dynamic structures formed by liquid-liquid phase separation (LLPS). Key drivers for LLPS in cells are multivalent protein:protein and protein:RNA interactions leading to specialized areas in the cell that recruit molecules with similar properties, while other non-similar molecules are excluded. These typical features of cellular biomolecular condensates are also a common characteristic in the biogenesis of viral inclusion bodies. Viral IBs are predominantly induced by the expression of the viral nucleoprotein (N, NP) and phosphoprotein (P); both are characterized by a special protein architecture containing multiple disordered regions and RNA-binding domains that contribute to different protein functions. P keeps N soluble after expression to allow a concerted binding of N to the viral RNA. This results in the encapsidation of the viral genome by N, while P acts additionally as a cofactor for the viral polymerase, enabling viral transcription and replication. Here, we will review the formation and function of those viral inclusion bodies upon infection with NSVs with respect to their nature as biomolecular condensates.
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Hardiman, Camille A., Justin A. McDonough, Hayley J. Newton, and Craig R. Roy. "The role of Rab GTPases in the transport of vacuoles containing Legionella pneumophila and Coxiella burnetii." Biochemical Society Transactions 40, no. 6 (November 21, 2012): 1353–59. http://dx.doi.org/10.1042/bst20120167.
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Intracellular pathogens survive in eukaryotic cells by evading a variety of host defences. To avoid degradation through the endocytic pathway, intracellular bacteria must adapt their phagosomes into protective compartments that promote bacterial replication. Legionella pneumophila and Coxiella burnetii are Gram-negative intracellular pathogens that remodel their phagosomes by co-opting components of the host cell, including Rab GTPases. L. pneumophila and C. burnetii are related phylogenetically and share an analogous type IV secretion system for delivering bacterial effectors into the host cell. Some of these effectors mimic eukaryotic biochemical activities to recruit and modify Rabs at the vacuole. In the present review, we cover how these bacterial species, which utilize divergent strategies to establish replicative vacuoles, use translocated proteins to manipulate host Rabs, as well as exploring which Rabs are implicated in vacuolar biogenesis in these two organisms.
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Iarovaia, Olga V., Elena S. Ioudinkova, Artem K. Velichko, and Sergey V. Razin. "Manipulation of Cellular Processes via Nucleolus Hijaking in the Course of Viral Infection in Mammals." Cells 10, no. 7 (June 25, 2021): 1597. http://dx.doi.org/10.3390/cells10071597.
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Due to their exceptional simplicity of organization, viruses rely on the resources, molecular mechanisms, macromolecular complexes, regulatory pathways, and functional compartments of the host cell for an effective infection process. The nucleolus plays an important role in the process of interaction between the virus and the infected cell. The interactions of viral proteins and nucleic acids with the nucleolus during the infection process are universal phenomena and have been described for almost all taxonomic groups. During infection, proteins of the nucleolus in association with viral components can be directly used for the processes of replication and transcription of viral nucleic acids and the assembly and transport of viral particles. In the course of a viral infection, the usurpation of the nucleolus functions occurs and the usurpation is accompanied by profound changes in ribosome biogenesis. Recent studies have demonstrated that the nucleolus is a multifunctional and dynamic compartment. In addition to the biogenesis of ribosomes, it is involved in regulating the cell cycle and apoptosis, responding to cellular stress, repairing DNA, and transcribing RNA polymerase II-dependent genes. A viral infection can be accompanied by targeted transport of viral proteins to the nucleolus, massive release of resident proteins of the nucleolus into the nucleoplasm and cytoplasm, the movement of non-nucleolar proteins into the nucleolar compartment, and the temporary localization of viral nucleic acids in the nucleolus. The interaction of viral and nucleolar proteins interferes with canonical and non-canonical functions of the nucleolus and results in a change in the physiology of the host cell: cell cycle arrest, intensification or arrest of ribosome biogenesis, induction or inhibition of apoptosis, and the modification of signaling cascades involved in the stress response. The nucleolus is, therefore, an important target during viral infection. In this review, we discuss the functional impact of viral proteins and nucleic acid interaction with the nucleolus during infection.
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Kujala, Pekka, Anne Ikäheimonen, Neda Ehsani, Helena Vihinen, Petri Auvinen, and Leevi Kääriäinen. "Biogenesis of the Semliki Forest Virus RNA Replication Complex." Journal of Virology 75, no. 8 (April 15, 2001): 3873–84. http://dx.doi.org/10.1128/jvi.75.8.3873-3884.2001.
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ABSTRACT The nonstructural (ns) proteins nsP1 to -4, the components of Semliki Forest virus (SFV) RNA polymerase, were localized in infected cells by confocal microscopy using double labeling with specific antisera against the individual ns proteins. All ns proteins were associated with large cytoplasmic vacuoles (CPV), the inner surfaces of which were covered by small invaginations, or spherules, typical of alphavirus infection. All ns proteins were localized by immuno-electron microscopy (EM) to the limiting membranes of CPV and to the spherules, together with newly labeled viral RNA. Along with earlier observations by EM-autoradiography (P. M. Grimley, I. K. Berezesky, and R. M. Friedman, J. Virol. 2:326–338, 1968), these results suggest that individual spherules represent template-associated RNA polymerase complexes. Immunoprecipitation of radiolabeled ns proteins showed that each antiserum precipitated the other three ns proteins, implying that they functioned as a complex. Double labeling with organelle-specific and anti-ns-protein antisera showed that CPV were derivatives of late endosomes and lysosomes. Indeed, CPV frequently contained endocytosed bovine serum albumin-coated gold particles, introduced into the medium at different times after infection. With time, increasing numbers of spherules were also observed on the cell surfaces; they were occasionally released into the medium, probably by secretory lysosomes. We suggest that the spherules arise by primary assembly of the RNA replication complexes at the plasma membrane, guided there by nsP1, which has affinity to lipids specific for the cytoplasmic leaflet of the plasma membrane. Endosomal recycling and fusion of CPV with the plasma membrane can circulate spherules between the plasma membrane and the endosomal-lysosomal compartment.
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Sasvari, Zsuzsanna, Nikolay Kovalev, Paulina Alatriste Gonzalez, Kai Xu, and Peter D. Nagy. "Assembly-hub function of ER-localized SNARE proteins in biogenesis of tombusvirus replication compartment." PLOS Pathogens 14, no. 5 (May 10, 2018): e1007028. http://dx.doi.org/10.1371/journal.ppat.1007028.
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Campoy, Emanuel Martín, Felipe Carlos Martín Zoppino, and María Isabel Colombo. "The Early Secretory Pathway Contributes to the Growth of theCoxiella-Replicative Niche." Infection and Immunity 79, no. 1 (October 11, 2010): 402–13. http://dx.doi.org/10.1128/iai.00688-10.
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ABSTRACTCoxiella burnetiiis a Gram-negative obligate intracellular bacterium. After internalization, this bacterium replicates in a large parasitophorous vacuole that has features of both phagolysosomes and autophagosomal compartments. We have previously demonstrated that early after internalizationCoxiellaphagosomes interact with both the endocytic and the autophagic pathways. In this report, we present evidence that theCoxiella-replicative vacuoles (CRVs) also interact with the secretory pathway. Rab1b is a small GTPase responsible for the anterograde transport between the endoplasmic reticulum and the Golgi apparatus. We present evidence that Rab1b is recruited to the CRV at later infection times (i.e., after 6 h of infection). Interestingly, knockdown of Rab1b altered vacuole growth, indicating that this protein was required for the proper biogenesis of the CRV. In addition, overexpression of the active GTPase-defective mutant (GFP-Rab1b Q67L) affected the development of theCoxiella-replicative compartment inhibiting bacterial growth. On the other hand, disruption of the secretory pathway by brefeldin A treatment or by overexpression of Sar1 T39N, a defective dominant-negative mutant of Sar1, affected the typical spaciousness of the CRVs. Taken together, our results show for the first time that theCoxiella-replicative niche also intercepts the early secretory pathway.
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Kagan, Jonathan C., Mary-Pat Stein, Marc Pypaert, and Craig R. Roy. "Legionella Subvert the Functions of Rab1 and Sec22b to Create a Replicative Organelle." Journal of Experimental Medicine 199, no. 9 (April 26, 2004): 1201–11. http://dx.doi.org/10.1084/jem.20031706.
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Legionella pneumophila is a bacterial pathogen that infects eukaryotic host cells and replicates inside a specialized organelle that is morphologically similar to the endoplasmic reticulum (ER). To better understand the molecular mechanisms governing transport of the Legionella-containing vacuole (LCV), we have identified host proteins that participate in the conversion of the LCV into a replicative organelle. Our data show that Rab1 is recruited to the LCV within minutes of uptake. Rab1 recruitment to the LCV precedes remodeling of this compartment by ER-derived vesicles. Genetic inhibition studies demonstrate that Rab1 is important for the recruitment of ER-derived vesicles to the LCV and that inhibiting Rab1 function abrogates intracellular growth of Legionella. Morphological studies indicate that the Sec22b protein is located on ER-derived vesicles recruited to the LCV and that Sec22b is delivered to the LCV membrane. Sec22b function was found to be important for biogenesis of the specialized organelle that supports Legionella replication. These studies demonstrate that Legionella has the ability to subvert Rab1 and Sec22b function to facilitate the transport and fusion of ER-derived vesicles with the LCV, resulting in the formation of a specialized organelle that can support bacterial replication.
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Trahey, Meg, Hyung Suk Oh, Craig E. Cameron, and Jesse C. Hay. "Poliovirus Infection Transiently Increases COPII Vesicle Budding." Journal of Virology 86, no. 18 (June 27, 2012): 9675–82. http://dx.doi.org/10.1128/jvi.01159-12.
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Poliovirus (PV) requires membranes of the host cell's secretory pathway to generate replication complexes (RCs) for viral RNA synthesis. Recent work identified the intermediate compartment and the Golgi apparatus as the precursors of the replication “organelles” of PV (N. Y. Hsu et al., Cell 141:799–811, 2010). In this study, we examined the effect of PV on COPII vesicles, the secretory cargo carriers that bud from the endoplasmic reticulum and homotypically fuse to form the intermediate compartment that matures into the Golgi apparatus. We found that infection by PV results in a biphasic change in functional COPII vesicle biogenesis in cells, with an early enhancement and subsequent inhibition. Concomitant with the early increase in COPII vesicle formation, we found an increase in the membrane fraction of Sec16A, a key regulator of COPII vesicle formation. We suggest that the early burst in COPII vesicle formation detected benefits PV by increasing the precursor pool required for the formation of its RCs.
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Tang, Yuyang, Ihid Carneiro Leao, Ebony M. Coleman, Robin Shepard Broughton, and James E. K. Hildreth. "Deficiency of Niemann-Pick Type C-1 Protein Impairs Release of Human Immunodeficiency Virus Type 1 and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments." Journal of Virology 83, no. 16 (May 27, 2009): 7982–95. http://dx.doi.org/10.1128/jvi.00259-09.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C-1 (NPC1)-deficient (NPCD) cells, wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments. We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release. Further, NPCD Epstein-Barr virus-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly compared to normal cells. Infection of the NPCD fibroblasts with a vesicular stomatitis virus G-pseudotyped strain of HIV-1 produced similar results, suggesting a postentry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release. Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.
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Shirt-Ediss, Ben, Sara Murillo-Sánchez, and Kepa Ruiz-Mirazo. "Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research." Beilstein Journal of Organic Chemistry 13 (July 13, 2017): 1388–95. http://dx.doi.org/10.3762/bjoc.13.135.
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Conceiving the process of biogenesis as the evolutionary development of highly dynamic and integrated protocell populations provides the most appropriate framework to address the difficult problem of how prebiotic chemistry bridged the gap to full-fledged living organisms on the early Earth. In this contribution we briefly discuss the implications of taking dynamic, functionally integrated protocell systems (rather than complex reaction networks in bulk solution, sets of artificially evolvable replicating molecules, or even these same replicating molecules encapsulated in passive compartments) as the proper units of prebiotic evolution. We highlight, in particular, how the organisational features of those chemically active and reactive protocells, at different stages of the process, would strongly influence their corresponding evolutionary capacities. As a result of our analysis, we suggest three experimental challenges aimed at constructing protocell systems made of a diversity of functionally coupled components and, thereby, at characterizing more precisely the type of prebiotic evolutionary dynamics that such protocells could engage in.
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Oostra, M., E. G. te Lintelo, M. Deijs, M. H. Verheije, P. J. M. Rottier, and C. A. M. de Haan. "Localization and Membrane Topology of Coronavirus Nonstructural Protein 4: Involvement of the Early Secretory Pathway in Replication." Journal of Virology 81, no. 22 (September 12, 2007): 12323–36. http://dx.doi.org/10.1128/jvi.01506-07.
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ABSTRACT The coronavirus nonstructural proteins (nsp's) derived from the replicase polyproteins collectively constitute the viral replication complexes, which are anchored to double-membrane vesicles. Little is known about the biogenesis of these complexes, the membrane anchoring of which is probably mediated by nsp3, nsp4, and nsp6, as they contain several putative transmembrane domains. As a first step to getting more insight into the formation of the coronavirus replication complex, the membrane topology, processing, and subcellular localization of nsp4 of the mouse hepatitis virus (MHV) and severe acute respiratory syndrome-associated coronavirus (SARS-CoV) were elucidated in this study. Both nsp4 proteins became N glycosylated, while their amino and carboxy termini were localized to the cytoplasm. These observations imply nsp4 to assemble in the membrane as a tetraspanning transmembrane protein with a Nendo/Cendo topology. The amino terminus of SARS-CoV nsp4, but not that of MHV nsp4, was shown to be (partially) processed by signal peptidase. nsp4 localized to the endoplasmic reticulum (ER) when expressed alone but was recruited to the replication complexes in infected cells. nsp4 present in these complexes did not colocalize with markers of the ER or Golgi apparatus, while the susceptibility of its sugars to endoglycosidase H indicated that the protein had also not traveled trough the latter compartment. The important role of the early secretory pathway in formation of the replication complexes was also demonstrated by the inhibition of coronaviral replication when the ER export machinery was blocked by use of the kinase inhibitor H89 or by expression of a mutant, Sar1[H79G].
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Weber, Mary M., Robert Faris, Erin J. van Schaik, Juanita Thrasher McLachlan, William U. Wright, Andres Tellez, Victor A. Roman, et al. "The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection." Infection and Immunity 84, no. 9 (June 20, 2016): 2524–33. http://dx.doi.org/10.1128/iai.01554-15.
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Coxiella burnetii, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretion system. Several effectors crucial forC. burnetiiintracellular replication have been identified, but the host pathways coopted by these essential effectors are poorly defined, and very little is known about how spacious vacuoles are formed and maintained. Here we demonstrate that the essential type IVb effector, CirA, stimulates GTPase activity of RhoA. Overexpression of CirA in mammalian cells results in cell rounding and stress fiber disruption, a phenotype that is rescued by overexpression of wild-type or constitutively active RhoA. Unlike other effector proteins that subvert Rho GTPases to modulate uptake, CirA is the first effector identified that is dispensable for uptake and instead recruits Rho GTPase to promote biogenesis of the bacterial vacuole. Collectively our results highlight the importance of CirA in coopting host Rho GTPases for establishment ofCoxiella burnetiiinfection and virulence in mammalian cell culture and mouse models of infection.
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Hood, David A. "Invited Review: Contractile activity-induced mitochondrial biogenesis in skeletal muscle." Journal of Applied Physiology 90, no. 3 (March 1, 2001): 1137–57. http://dx.doi.org/10.1152/jappl.2001.90.3.1137.
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Chronic contractile activity produces mitochondrial biogenesis in muscle. This adaptation results in a significant shift in adenine nucleotide metabolism, with attendant improvements in fatigue resistance. The vast majority of mitochondrial proteins are derived from the nuclear genome, necessitating the transcription of genes, the translation of mRNA into protein, the targeting of the protein to a mitochondrial compartment via the import machinery, and the assembly of multisubunit enzyme complexes in the respiratory chain or matrix. Putative signals involved in initiating this pathway of gene expression in response to contractile activity likely arise from combinations of accelerations in ATP turnover or imbalances between mitochondrial ATP synthesis and cellular ATP demand, and Ca2+ fluxes. These rapid events are followed by the activation of exercise-responsive kinases, which phosphorylate proteins such as transcription factors, which subsequently bind to upstream regulatory regions in DNA, to alter transcription rates. Contractile activity increases the mRNA levels of nuclear-encoded proteins such as cytochrome c and mitochondrial transcription factor A (Tfam) and mRNA levels of upstream transcription factors like c- junand nuclear respiratory factor-1 (NRF-1). mRNA level changes are often most evident during the postexercise recovery period, and they can occur as a result of contractile activity-induced increases in transcription or mRNA stability. Tfam is imported into mitochondria and controls the expression of mitochondrial DNA (mtDNA). mtDNA contributes only 13 protein products to the respiratory chain, but they are vital for electron transport and ATP synthesis. Contractile activity increases Tfam expression and accelerates its import into mitochondria, resulting in increased mtDNA transcription and replication. The result of this coordinated expression of the nuclear and the mitochondrial genomes, along with poorly understood changes in phospholipid synthesis, is an expansion of the muscle mitochondrial reticulum. Further understanding of 1) regulation of mtDNA expression, 2) upstream activators of NRF-1 and other transcription factors, 3) the identity of mRNA stabilizing proteins, and 4) potential of contractile activity-induced changes in apoptotic signals are warranted.
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Jarvis, Michael A., Thomas R. Jones, Derek D. Drummond, Patsy P. Smith, William J. Britt, Jay A. Nelson, and Carl J. Baldick. "Phosphorylation of Human Cytomegalovirus Glycoprotein B (gB) at the Acidic Cluster Casein Kinase 2 Site (Ser900) Is Required for Localization of gB to the trans-Golgi Network and Efficient Virus Replication." Journal of Virology 78, no. 1 (January 1, 2004): 285–93. http://dx.doi.org/10.1128/jvi.78.1.285-293.2004.
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ABSTRACT Human cytomegalovirus (HCMV) glycoprotein B (gB), encoded by the UL55 open reading frame, is an essential envelope glycoprotein involved in cell attachment and entry. Previously, we identified residue serine 900 (Ser900) as a unique site of reversible casein kinase 2 phosphorylation in the cytoplasmic domain of HCMV gB. We have also recently shown that gB is localized to the trans-Golgi network (TGN) in HCMV-permissive cells, thereby identifying the TGN as a possible site of virus envelopment. The aim of the current study was to determine the role of Ser900 phosphorylation in transport of gB to the TGN and in HCMV biogenesis. Recombinant HCMV strains were constructed that expressed gB molecules containing either an aspartic acid (gBAsp900) or alanine residue (gBAla900) substitution at Ser900 to mimic the phosphorylated or nonphosphorylated form, respectively. Immunofluorescence analysis of the trafficking of gB mutant molecules in fibroblasts infected with the HCMV recombinants revealed that gBAsp900 was localized to the TGN. In contrast, gBAla900 was partially mislocalized from the TGN, indicating that phosphorylation of gB at Ser900 was necessary for TGN localization. The increased TGN localization of gBAsp900 was due to a decreased transport of the molecule to post-TGN compartments. Remarkably, the substitution of an aspartic acid residue for Ser900 also resulted in an increase in levels of progeny virus production during HCMV infection of fibroblasts. Together, these results demonstrate that phosphorylation of gB at Ser900 is necessary for gB localization to the TGN, as well as for efficient viral replication, and further support the TGN as a site of HCMV envelopment.
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Pène, Véronique, Qisheng Li, Catherine Sodroski, Ching-Sheng Hsu, and T. Jake Liang. "Dynamic Interaction of Stress Granules, DDX3X, and IKK-α Mediates Multiple Functions in Hepatitis C Virus Infection." Journal of Virology 89, no. 10 (March 4, 2015): 5462–77. http://dx.doi.org/10.1128/jvi.03197-14.
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ABSTRACTThe ubiquitous ATP-dependent RNA helicase DDX3X is involved in many cellular functions, including innate immunity, and is a pivotal host factor for hepatitis C virus (HCV) infection. Recently, we showed that DDX3X specifically recognizes the HCV 3′ untranslated region (UTR), leading to the activation of IKK-α and a cascade of lipogenic signaling to facilitate lipid droplet biogenesis and viral assembly (Q. Li, V. Pene, S. Krishnamurthy, H. Cha, and T. J. Liang, Nat Med19:722–729, 2013,http://dx.doi.org/10.1038/nm.3190). The interaction of DDX3X with HCV core protein seems to be dispensable for its proviral role. In this study, through systematic imaging and biochemical and virologic approaches, we identified a dynamic association between DDX3X and various cellular compartments and viral elements mediating multiple functions of DDX3X in productive HCV infection. Upon HCV infection, the HCV 3′UTR interacts with DDX3X and IKK-α, which redistribute to speckle-like cytoplasmic structures shown to be stress granules (SGs). As viral proteins accumulate in infected cells, DDX3X granules together with SG-associated proteins redistribute and colocalize with HCV core protein around lipid droplets (LDs). IKK-α, however, does not relocate to the LD but translocates to the nucleus. In HCV-infected cells, various HCV nonstructural proteins also interact or colocalize with DDX3X in close proximity to SGs and LDs, consistent with the tight juxtaposition of the replication complex and the assembly site at the surface of LDs. Short interfering RNA (siRNA)-mediated silencing of DDX3X and multiple SG components markedly inhibits HCV infection. Our data suggest that DDX3X initiates a multifaceted cellular program involving dynamic associations with HCV RNA and proteins, IKK-α, SG, and LD surfaces for its crucial role in the HCV life cycle.IMPORTANCEDDX3X is a proviral host factor for HCV infection. Recently, we showed that DDX3X binds to the HCV 3′UTR, activating IKK-α and cellular lipogenesis to facilitate viral assembly (Q. Li et al., Nat Med19:722–729, 2013,http://dx.doi.org/10.1038/nm.3190). Here, we report associations of DDX3X with various cellular compartments and viral elements that mediate its multiple functions in the HCV life cycle. Upon infection, the HCV 3′UTR redistributes DDX3X and IKK-α to speckle-like cytoplasmic structures shown to be SGs. Subsequently, interactions between DDX3X, SG, and HCV proteins facilitate the translocation of DDX3X-SG complexes to the LD surface. HCV nonstructural proteins are shown to colocalize with DDX3X in close proximity to SGs and LDs, consistent with the tight juxtaposition of the HCV replication complex and assembly site at the LD surface. Our data demonstrate that DDX3X initiates a multifaceted cellular program involving dynamic associations with HCV elements, IKK-α, SGs, and LDs for its critical role in HCV infection.
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Chao, Hengjun, and Johnson M. Liu. "Premature Senescence in Hematopoietic Stem and Progenitor Cells in Ribosomopathy-Associated Bone Marrow Failure Syndromes." Blood 126, no. 23 (December 3, 2015): 298. http://dx.doi.org/10.1182/blood.v126.23.298.298.
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Abstract Introduction: Aged hematopoietic stem cells (HSCs) are known to functionally decline and are prone to development of myeloid malignancies. Recent work has highlighted the twin roles of replication stress and decreased ribosome biogenesis as drivers for the accumulation of DNA damage and senescence. Certain bone marrow failure syndromes, including Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), and the acquired 5q- syndrome, are characterized by defects in ribosome biogenesis. Furthermore, recent work has suggested a role for p53 activation, through the 5S ribonucleoprotein particle (RNP), in driving cells to senescence following perturbation of ribosome biogenesis. Methods and Results: Here, we have used multiplexing flow cytometry protocols to define, enumerate, and characterize hematopoietic cells of distinct differentiation stages and lineages in 2 DBA cord bloods and 4 adult bone marrows (2 SDS, 1 DBA, and 1 patient with a diminutive somatic deletion of 5q: ages 27, 32, 40, and 30, respectively), as compared with 4 normal cord bloods and 6 normal adult bone marrows. We included a patient with bona fide MDS (diminutive somatic deletion of 5q including RPS14 in a young adult) to compare with the SDS and DBA patients, who do not meet criteria for MDS. Our preliminary results revealed significant defects in the primitive HSC and multipotent progenitor (MPP) compartments in both DBA and SDS. Specifically, we found in DBA and SDS bone marrow and cord blood samples (compared to normal controls): significantly decreased numbers of primitive HSCs (Lin-CD34+CD133+CD38-CD45RA-CD49f+CD90+) and MPPs (Lin-CD34+CD133+CD38-CD45RA-CD49f-CD90-); increased levels of apoptosis and dysregulated proliferation; and G0-1/S cell cycle arrest. We also found significant increases in senescence-associated β-galactosidase staining and G0-1/S cell cycle arrest in Lin-CD34+ and Lin-CD34+CD38-CD133+ subpopulations in all 4 adult patient bone marrows, as compared with normal adult bone marrows processed in identical fashion [see Fig. 1 for representative data from Lin-CD34+CD133+ hematopoietic progenitor cells (HPCs) from one SDS patient]. Foci of the phosphorylated form of the variant histone H2AX (γH2AX) mark DNA damage, and γH2AX staining was similarly increased in comparison to controls (Fig. 1). The mechanism whereby disturbed ribosome biogenesis induces senescence has been suggested as involving 5S RNP-mediated p53 activation. However, our experiments did not demonstrate increased levels of p53 in the SDS patient marrows, as assessed by intracellular staining. Levels of p16, a well known marker of senescence, were markedly increased in the SDS patient samples, when compared to controls. Finally, in the 2 DBA cord bloods analyzed, there was increased senescence-associated β-galactosidase staining but to a lesser degree than in the adult bone marrow samples (as might be expected with temporal progression). Discussion: Taken together, our data suggest that ribosomopathies (which often present in childhood) are disorders of premature senescence. Consequent DNA damage accumulation and decreased repair and compensation may account for the development of MDS and acute myeloid leukemia, disorders seen in young ribosomopathy patients that ordinarily are rare in the general pediatric and young adult population. Disclosures No relevant conflicts of interest to declare.
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Mackenzie, Jason M., Malcolm K. Jones, and Edwin G. Westaway. "Markers for trans-Golgi Membranes and the Intermediate Compartment Localize to Induced Membranes with Distinct Replication Functions in Flavivirus-Infected Cells." Journal of Virology 73, no. 11 (November 1, 1999): 9555–67. http://dx.doi.org/10.1128/jvi.73.11.9555-9567.1999.
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ABSTRACT Replication of the flavivirus Kunjin virus is associated with virus-induced membrane structures within the cytoplasm of infected cells; these membranes appear as packets of vesicles associated with the sites of viral RNA synthesis and as convoluted membranes (CM) and paracrystalline arrays (PC) containing the components of the virus-specified protease (E. G. Westaway, J. M. Mackenzie, M. T. Kenney, M. K. Jones, and A. A. Khromykh, J. Virol. 71:6650–6661, 1997). To determine the cellular origins of these membrane structures, we compared the immunolabelling patterns of several cell markers in relation to these sites by immunofluorescence and immunoelectron microscopy. A marker for the trans-Golgi membranes and the trans-Golgi network, 1,4-galactosyltransferase (GalT), was redistributed to large foci in the cytoplasm of Kunjin virus-infected cells, partially coincident with immunofluorescent foci associated with the putative sites of viral RNA synthesis. As determined by immunoelectron microscopy, the induced vesicle packets contained GalT, whereas the CM and PC contained a specific protein marker for the intermediate compartment (ERGIC53). A further indicator of the role of cellular organelles in their biogenesis was the observation that the Golgi apparatus-disrupting agent brefeldin A prevented further development of immunofluorescent foci of induced membranes if added before the end of the latent period but that once formed, these membrane foci were resistant to brefeldin A dispersion. Reticulum membranes emanating from the induced CM and PC were also labelled with the rough endoplasmic reticulum marker anti-protein disulfide isomerase and were obviously redistributed during infection. This is the first report identifyingtrans-Golgi membranes and the intermediate compartment as the apparent sources of the flavivirus-induced membranes involved in events of replication.
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Celli, Jean, Chantal de Chastellier, Don-Marc Franchini, Javier Pizarro-Cerda, Edgardo Moreno, and Jean-Pierre Gorvel. "Brucella Evades Macrophage Killing via VirB-dependent Sustained Interactions with the Endoplasmic Reticulum." Journal of Experimental Medicine 198, no. 4 (August 18, 2003): 545–56. http://dx.doi.org/10.1084/jem.20030088.
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The intracellular pathogen Brucella is the causative agent of brucellosis, a worldwide zoonosis that affects mammals, including humans. Essential to Brucella virulence is its ability to survive and replicate inside host macrophages, yet the underlying mechanisms and the nature of the replicative compartment remain unclear. Here we show in a model of Brucella abortus infection of murine bone marrow–derived macrophages that a fraction of the bacteria that survive an initial macrophage killing proceed to replicate in a compartment segregated from the endocytic pathway. The maturation of the Brucella-containing vacuole involves sustained interactions and fusion with the endoplasmic reticulum (ER), which creates a replicative compartment with ER-like properties. The acquisition of ER membranes by replicating Brucella is independent of ER-Golgi COPI-dependent vesicular transport. A mutant of the VirB type IV secretion system, which is necessary for intracellular survival, was unable to sustain interactions and fuse with the ER, and was killed via eventual fusion with lysosomes. Thus, we demonstrate that live intracellular Brucella evade macrophage killing through VirB-dependent sustained interactions with the ER. Moreover, we assign an intracellular function to the VirB system, as being required for late maturation events necessary for the biogenesis of an ER-derived replicative organelle.
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Schmid, M., T. Speiseder, T. Dobner, and R. A. Gonzalez. "DNA Virus Replication Compartments." Journal of Virology 88, no. 3 (November 20, 2013): 1404–20. http://dx.doi.org/10.1128/jvi.02046-13.
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McNamee, Elizabeth E., Travis J. Taylor, and David M. Knipe. "A Dominant-Negative Herpesvirus Protein Inhibits Intranuclear Targeting of Viral Proteins: Effects on DNA Replication and Late Gene Expression." Journal of Virology 74, no. 21 (November 1, 2000): 10122–31. http://dx.doi.org/10.1128/jvi.74.21.10122-10131.2000.
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ABSTRACT The d105 dominant-negative mutant form of the herpes simplex virus 1 (HSV-1) single-stranded DNA-binding protein, ICP8 (d105 ICP8), inhibits wild-type viral replication, and it blocks both viral DNA replication and late gene transcription, although to different degrees (M. Gao and D. M. Knipe, J. Virol. 65:2666–2675, 1991; Y. M. Chen and D. M. Knipe, Virology 221:281–290, 1996). We demonstrate here that this protein is also capable of preventing the formation of intranuclear prereplicative sites and replication compartments during HSV infection. We defined three patterns of ICP8 localization using indirect immunofluorescence staining of HSV-1-infected cells: large replication compartments, small compartments, and no specific intranuclear localization of ICP8. Cells that form large replication compartments replicate viral DNA and express late genes. Cells that form small replication compartments replicate viral DNA but do not express late genes, while cells without viral replication compartments are incapable of both DNA replication and late gene expression. The d105 ICP8 protein blocks formation of prereplicative sites and large replication compartments in 80% of infected cells and formation of large replication compartments in the remaining 20% of infected cells. The phenotype ofd105 suggests a correlation between formation of large replication compartments and late gene expression and a role for intranuclear rearrangement of viral DNA and bound proteins in activation of late gene transcription. Thus, these results provide evidence for specialized machinery for late gene expression within replication compartments.
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Daikoku, Tohru, Ayumi Kudoh, Masatoshi Fujita, Yutaka Sugaya, Hiroki Isomura, Noriko Shirata, and Tatsuya Tsurumi. "Architecture of Replication Compartments Formed during Epstein-Barr Virus Lytic Replication." Journal of Virology 79, no. 6 (March 15, 2005): 3409–18. http://dx.doi.org/10.1128/jvi.79.6.3409-3418.2005.
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ABSTRACT Epstein-Barr virus (EBV) productive DNA replication occurs at discrete sites, called replication compartments, in nuclei. In this study we performed comprehensive analyses of the architecture of the replication compartments. The BZLF1 oriLyt binding proteins showed a fine, diffuse pattern of distribution throughout the nuclei at immediate-early stages of induction and then became associated with the replicating EBV genome in the replication compartments during lytic infection. The BMRF1 polymerase (Pol) processivity factor showed a homogenous, not dot-like, distribution in the replication compartments, which completely coincided with the newly synthesized viral DNA. Inhibition of viral DNA replication with phosphonoacetic acid, a viral DNA Pol inhibitor, eliminated the DNA-bound form of the BMRF1 protein, although the protein was sufficiently expressed in the cells. These observations together with the findings that almost all abundantly expressed BMRF1 proteins existed in the DNA-bound form suggest that the BMRF1 proteins not only act at viral replication forks as Pol processive factors but also widely distribute on newly replicated EBV genomic DNA. In contrast, the BALF5 Pol catalytic protein, the BALF2 single-stranded-DNA binding protein, and the BBLF2/3 protein, a component of the helicase-primase complex, were colocalized as distinct dots distributed within replication compartments, representing viral replication factories. Whereas cellular replication factories are constructed based on nonchromatin nuclear structures and nuclear matrix, viral replication factories were easily solubilized by DNase I treatment. Thus, compared with cellular DNA replication, EBV lytic DNA replication factories would be simpler so that construction of the replication domain would be more relaxed.
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Hidalgo, Paloma, and Ramón A. Gonzalez. "Formation of adenovirus DNA replication compartments." FEBS Letters 593, no. 24 (November 26, 2019): 3518–30. http://dx.doi.org/10.1002/1873-3468.13672.
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Nagaraju, Thejaswi, Arthur U. Sugden, and Bill Sugden. "Four-dimensional analyses show that replication compartments are clonal factories in which Epstein–Barr viral DNA amplification is coordinated." Proceedings of the National Academy of Sciences 116, no. 49 (November 19, 2019): 24630–38. http://dx.doi.org/10.1073/pnas.1913992116.
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Herpesviruses must amplify their DNA to load viral particles and they do so in replication compartments. The development and functions of replication compartments during DNA amplification are poorly understood, though. Here we examine 2 functionally distinct replicons in the same cells to dissect DNA amplification within replication compartments. Using a combination of single-cell assays, computational modeling, and population approaches, we show that compartments initially were seeded by single genomes of Epstein–Barr virus (EBV). Their amplification subsequently took 13 to 14 h in individual cells during which their compartments occupied up to 30% of the nucleus and the nuclear volume grew by 50%. The compartmental volumes increased in proportion to the amount of DNA and viral replication proteins they contained. Each compartment synthesized similar levels of DNA, indicating that the total number of compartments determined the total levels of DNA amplification. Further, the amplification, which depended on the number of origins, was regulated differently early and late during the lytic phase; early during the lytic phase, the templates limited DNA synthesis, while later the templates were in excess, coinciding with a decline in levels of the viral replication protein, BMRF1, in the replication compartments. These findings show that replication compartments are factories in which EBV DNA amplification is both clonal and coordinated.
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Fraefel, Cornel, Anne Greet Bittermann, Hansruedi Büeler, Irma Heid, Thomas Bächi, and Mathias Ackermann. "Spatial and Temporal Organization of Adeno-Associated Virus DNA Replication in Live Cells." Journal of Virology 78, no. 1 (January 1, 2004): 389–98. http://dx.doi.org/10.1128/jvi.78.1.389-398.2004.
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ABSTRACT Upon cell entry, the genomes of herpes simplex virus type 1 (HSV-1) and adenovirus (Ad) associate with distinct nuclear structures termed ND10 or promyelocytic leukemia (PML) nuclear bodies (NBs). PML NB morphology is altered or disrupted by specific viral proteins as replication proceeds. We examined whether adeno-associated virus (AAV) replication compartments also associate with PML NBs, and whether modification or disruption of these by HSV-1 or Ad, both of which are helper viruses for AAV, is necessary at all. Furthermore, to add a fourth dimension to our present view of AAV replication, we established an assay that allows visualization of AAV replication in live cells. A recombinant AAV containing 40 lac repressor binding sites between the AAV inverted terminal repeats was constructed. AAV Rep protein and helper virus-mediated replication of this recombinant AAV genome was visualized by binding of enhanced yellow fluorescent protein-lac repressor fusion protein to double-stranded AAV replication intermediates. We demonstrate in live cells that AAV DNA replication occurs in compartments which colocalize with AAV Rep. Early after infection, the replication compartments were small and varied in numbers from 2 to more than 40 per cell nucleus. Within 4 to 8 h, individual small replication compartments expanded and fused to larger structures which filled out much of the cell nucleus. We also show that AAV replication compartments can associate with modified PML NBs in Ad-infected cells. In wild-type HSV-1-infected cells, AAV replication compartments and PML NBs did not coexist, presumably because PML was completely disrupted by the HSV-1 ICP0 protein. However, alteration or disruption of PML appears not to be a prerequisite for AAV replication, as the formation of replication compartments was normal when the ICP0 mutants HSV-1 dl1403 and HSV-1 FXE, which do not affect PML NBs, were used as the helper viruses; under these conditions, AAV replication compartments did not associate with PML NBs.
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van der Hoeven, Barbara, Diede Oudshoorn, Abraham J. Koster, Eric J. Snijder, Marjolein Kikkert, and Montserrat Bárcena. "Biogenesis and architecture of arterivirus replication organelles." Virus Research 220 (July 2016): 70–90. http://dx.doi.org/10.1016/j.virusres.2016.04.001.
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Burkham, Jennifer, Donald M. Coen, Charles B. C. Hwang, and Sandra K. Weller. "Interactions of Herpes Simplex Virus Type 1 with ND10 and Recruitment of PML to Replication Compartments." Journal of Virology 75, no. 5 (March 1, 2001): 2353–67. http://dx.doi.org/10.1128/jvi.75.5.2353-2367.2001.
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ABSTRACT Many of the events required for productive herpes simplex virus type 1 (HSV-1) infection occur within globular nuclear domains called replication compartments, whose formation appears to depend on interactions with cellular nuclear domains 10 (ND10). We have previously demonstrated that the formation of HSV-1 replication compartments involves progression through several stages, including the disruption of intact ND10 (stage I to stage II) and the formation of PML-associated prereplicative sites (stage III) and replication compartments (stage IV) (J. Burkham, D. M. Coen, and S. K. Weller, J. Virol. 72:10100–10107, 1998). In this paper, we show that some, but not all, PML isoforms are recruited to stage III foci and replication compartments. Genetic experiments showed that the recruitment of PML isoforms to stage III prereplicative sites and replication compartments requires the localization of the HSV-1 polymerase protein (UL30) to these foci but does not require polymerase catalytic activity. We also examined the stages of viral infection under conditions affecting ND10 integrity. Treatment with factors that increase the stability of ND10, arsenic trioxide and the proteasome inhibitor MG132, inhibited viral disruption of ND10, formation of replication compartments, and production of progeny virus. These results strengthen the previously described correlation between ND10 disruption and productive viral infection.
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Shulla, Ana, and Glenn Randall. "(+) RNA virus replication compartments: a safe home for (most) viral replication." Current Opinion in Microbiology 32 (August 2016): 82–88. http://dx.doi.org/10.1016/j.mib.2016.05.003.
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Swindle, C. Scott, Nianxiang Zou, Brian A. Van Tine, George M. Shaw, Jeffrey A. Engler, and Louise T. Chow. "Human Papillomavirus DNA Replication Compartments in a Transient DNA Replication System." Journal of Virology 73, no. 2 (February 1, 1999): 1001–9. http://dx.doi.org/10.1128/jvi.73.2.1001-1009.1999.
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ABSTRACT Many DNA viruses replicate their genomes at nuclear foci in infected cells. Using indirect immunofluorescence in combination with fluorescence in situ hybridization, we colocalized the human papillomavirus (HPV) replicating proteins E1 and E2 and the replicating origin-containing plasmid to nuclear foci in transiently transfected cells. The host replication protein A (RP-A) was also colocalized to these foci. These nuclear structures were identified as active sites of viral DNA synthesis by bromodeoxyuridine (BrdU) pulse-labeling. Unexpectedly, the great majority of RP-A and BrdU incorporation was found in these HPV replication domains. Furthermore, E1, E2, and RP-A were also colocalized to nuclear foci in the absence of an origin-containing plasmid. These observations suggest a spatial reorganization of the host DNA replication machinery upon HPV DNA replication or E1 and E2 expression. Alternatively, viral DNA replication might be targeted to host nuclear domains that are active during the late S phase, when such domains are limited in number. In a fraction of cells expressing E1 and E2, the promyelocytic leukemia protein, a component of nuclear domain 10 (ND10), was either partially or completely colocalized with E1 and E2. Since ND10 structures were recently hypothesized to be sites of bovine papillomavirus virion assembly, our observation suggests that HPV DNA amplification might be partially coupled to virion assembly.
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Taylor, Travis J., Elizabeth E. McNamee, Cheryl Day, and David M. Knipe. "Herpes simplex virus replication compartments can form by coalescence of smaller compartments." Virology 309, no. 2 (May 2003): 232–47. http://dx.doi.org/10.1016/s0042-6822(03)00107-7.
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Nagaraju, Thejaswi, Arthur Sugden, and Bill Sugden. "4D Analyses Show That Replication Compartments Are Clonal Factories in Which Epstein–Barr Viral DNA Amplification Is Coordinated." Proceedings 50, no. 1 (August 7, 2020): 140. http://dx.doi.org/10.3390/proceedings2020050140.
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Most DNA viruses must amplify their DNA to form new viral particles. To kickstart their DNA amplification, herpesviruses alter the host cell cycle dynamics by halting G1/S progression. Soon after, the viruses begin amplifying their DNA and halt any detectable cellular DNA synthesis. Viral DNA amplification takes place in specialized regions of the cell known as replication compartments. The genesis and maturation of replication compartments are not well understood. While replication compartments can only be visualized via microscopy, examining DNA synthetic events requires ensemble approaches. We have therefore exploited single-cell assays, including live-cell imaging, fluorescence in situ hybridization (FISH), and EdU-pulse labeling, in combination with computational simulations and ensemble approaches, to study the role of replication compartments in the DNA amplification of the Epstein–Barr virus (EBV). FISH revealed that each replication compartment initially contained a single DNA molecule which did not travel between compartments. DNA amplification lasted for 13–14 h in single cells, as shown by live cell imaging. Replication compartments eventually grew to occupy 30% of the nucleus, which itself grew by 50%. We found that early in the lytic phase, the availability of DNA templates limited DNA synthesis, while late in the lytic phase, the majority of viral DNA molecules no longer served as templates, which correlated with a drop in the levels of the replication protein. The eventual decline in DNA synthesis did not result from encapsidation; only 1–2% of the viral DNA was encapsidated. The levels of viral DNA synthesis in each compartment were similar. Therefore, the number of compartments determined the total amount of DNA synthesized and, consequently, the levels of amplified DNA. This finding was predicted by computational simulations of the amplification of the two distinct EBV derived replicons that we studied. Our results establish that replication compartments represent clonal factories for DNA amplification that are regulated coordinately during the lytic phase.
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Glauser, Daniel L., Regina Strasser, Andrea S. Laimbacher, Okay Saydam, Nathalie Clément, R. Michael Linden, Mathias Ackermann, and Cornel Fraefel. "Live Covisualization of Competing Adeno-Associated Virus and Herpes Simplex Virus Type 1 DNA Replication: Molecular Mechanisms of Interaction." Journal of Virology 81, no. 9 (February 21, 2007): 4732–43. http://dx.doi.org/10.1128/jvi.02476-06.
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ABSTRACT We performed live cell visualization assays to directly assess the interaction between competing adeno-associated virus (AAV) and herpes simplex virus type 1 (HSV-1) DNA replication. Our studies reveal the formation of separate AAV and HSV-1 replication compartments and the inhibition of HSV-1 replication compartment formation in the presence of AAV. AAV Rep is recruited into AAV replication compartments but not into those of HSV-1, while the single-stranded DNA-binding protein HSV-1 ICP8 is recruited into both AAV and HSV-1 replication compartments, although with differential staining patterns. Slot blot analysis of coinfected cells revealed a dose-dependent inhibition of HSV-1 DNA replication by wild-type AAV but not by rep-negative recombinant AAV. Consistent with this, Western blot analysis indicated that wild-type AAV affects the levels of the HSV-1 immediate-early protein ICP4 and the early protein ICP8 only modestly but strongly inhibits the accumulation of the late proteins VP16 and gC. Furthermore, we demonstrate that the presence of Rep in the absence of AAV DNA replication is sufficient for the inhibition of HSV-1. In particular, Rep68/78 proteins severely inhibit the formation of mature HSV-1 replication compartments and lead to the accumulation of ICP8 at sites of cellular DNA synthesis, a phenomenon previously observed in the presence of viral polymerase inhibitors. Taken together, our results suggest that AAV and HSV-1 replicate in separate compartments and that AAV Rep inhibits HSV-1 at the level of DNA replication.
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Tenorio, Raquel, Isabel Fernández de Castro, Jonathan J. Knowlton, Paula F. Zamora, Danica M. Sutherland, Cristina Risco, and Terence S. Dermody. "Function, Architecture, and Biogenesis of Reovirus Replication Neoorganelles." Viruses 11, no. 3 (March 21, 2019): 288. http://dx.doi.org/10.3390/v11030288.
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Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release of progeny particles. Reoviruses are common pathogens of mammals that have been linked to celiac disease and show promise for oncolytic applications. These viruses form nonenveloped, double-shelled virions that contain ten segments of double-stranded RNA. Replication organelles in reovirus-infected cells are nucleated by viral nonstructural proteins µNS and σNS. Both proteins partition the endoplasmic reticulum to form the matrix of these structures. The resultant membranous webs likely serve to anchor viral RNA–protein complexes for the replication of the reovirus genome and the assembly of progeny virions. Ongoing studies of reovirus replication organelles will advance our knowledge about the strategies used by viruses to commandeer host biosynthetic pathways and may expose new targets for therapeutic intervention against diverse families of pathogenic viruses.
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Sant'Anna, Celso, Wanderley de Souza, and Narcisa Cunha-e-Silva. "Biogenesis of the Reservosomes of Trypanosoma cruzi." Microscopy and Microanalysis 10, no. 5 (October 2004): 637–46. http://dx.doi.org/10.1017/s1431927604040863.
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Reservosomes are endocytic compartments found in the posterior region of epimastigotes of Trypanosoma cruzi. In the differentiation from trypomastigotes to epimastigotes (reverse metacyclogenesis in vitro), one has the rare opportunity of following the biogenesis of an endocytic compartment. Metacyclic trypomastigotes incubated in LIT medium highly enriched with fetal calf serum differentiated directly to epimastigotes. In recently differentiated epimastigotes, acidic organelles were found in round compartments spread along the cell body, whereas in control epimastigotes they were found in reservosomes located in the posterior region. Ultrastructural analysis of intermediate forms showed that the cytostome and reservosomes appeared before differentiation to epimastigotes was completed. Many polymorphic reservosomes, with or without lipid inclusions, were observed from the anterior portion of the cell body, in close relationship with the Golgi complex, to the posterior region. Endocytic tracers were observed in the cytostome, flagellar pocket, vesicles, and newly formed reservosomes. Cruzipain, the main protease of T. cruzi, was localized in newly formed reservosomes and in vesicles budding from the trans-Golgi network that seem to fuse with reservosomes. Ingested gold-labeled albumin and cruzipain colocalized in recently formed reservosomes. Endocytosis and immunocytochemical analysis suggested that the endocytic and the secretory pathways may contribute to reservosome formation.
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Darwish, Anthar S., Lorry M. Grady, Ping Bai, and Sandra K. Weller. "ICP8 Filament Formation Is Essential for Replication Compartment Formation during Herpes Simplex Virus Infection." Journal of Virology 90, no. 5 (December 16, 2015): 2561–70. http://dx.doi.org/10.1128/jvi.02854-15.
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ABSTRACTHerpes simplex virus (HSV) dramatically reorganizes the infected-cell nucleus, leading to the formation of prereplicative sites and replication compartments. This process is driven by the essential viral single-stranded DNA (ssDNA) binding protein ICP8, which can form double-helical filaments in the absence of DNA. In this paper, we show that two conserved motifs, FNF (F1142, N1143, and F1144) and FW (F843 and W844), are essential for ICP8 self-interactions, and we propose that the FNF motif docks into the FW region during filament formation. Mammalian expression plasmids bearing mutations in these motifs (FNF and FW) were unable to complement an ICP8-null mutant for growth and replication compartment formation. Furthermore, FNF and FW mutants were able to inhibit wild-type (WT) virus plaque formation and filament formation, whereas a double mutant (FNF-FW) was not. These results suggest that single mutant proteins are incorporated into nonproductive ICP8 filaments, while the double mutant is unable to interact with WT ICP8 and does not interfere with WT growth. Cells transfected with WT ICP8 and the helicase-primase (H/P) complex exhibited punctate nuclear structures that resemble prereplicative sites; however, the FNF and FW mutants failed to do so. Taken together, these results suggest that the FNF and FW motifs are required for ICP8 self-interactions and that these interactions may be important for the formation of prereplicative sites and replication compartments. We propose that filaments or other higher-order structures of ICP8 may provide a scaffold onto which other proteins can be recruited to form prereplicative sites and replication compartments.IMPORTANCEFor nuclear viruses such as HSV, efficient DNA replication requires the formation of discrete compartments within the infected-cell nucleus in which replication proteins are concentrated and assembled into the HSV replisome. In this paper, we characterize the role of filament formation by the single-stranded DNA binding protein ICP8 in the formation of prereplicative sites and replication compartments. We propose that ICP8 protein filaments generate a protein scaffold for other cellular and viral proteins, resulting in a structure that concentrates both viral DNA and replication proteins. Replication compartments may be similar to other types of cellular membraneless compartments thought to be formed by phase separations caused by low-affinity, multivalent interactions involving proteins and nucleic acids within cells. ICP8 scaffolds could facilitate the formation of replication compartments by mediating interactions with other components of the replication machinery.
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Ruban-Ośmiałowska, Beata, Dagmara Jakimowicz, Aleksandra Smulczyk-Krawczyszyn, Keith F. Chater, and Jolanta Zakrzewska-Czerwińska. "Replisome Localization in Vegetative and Aerial Hyphae of Streptomyces coelicolor." Journal of Bacteriology 188, no. 20 (October 1, 2006): 7311–16. http://dx.doi.org/10.1128/jb.00940-06.
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ABSTRACT Using a functional fusion of DnaN to enhanced green fluorescent protein, we examined the subcellular localization of the replisome machinery in the vegetative mycelium and aerial mycelium of the multinucleoid organism Streptomyces coelicolor. Chromosome replication took place in many compartments of both types of hypha, with the apical compartments of the aerial mycelium exhibiting the highest replication activity. Within a single compartment, the number of “current” ongoing DNA replications was lower than the expected chromosome number, and the appearance of fluorescent foci was often heterogeneous, indicating that this process is asynchronous within compartments and that only selected chromosomes undergo replication.
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Mast, Fred D., Andrei Fagarasanu, Barbara Knoblach, and Richard A. Rachubinski. "Peroxisome Biogenesis: Something Old, Something New, Something Borrowed." Physiology 25, no. 6 (December 2010): 347–56. http://dx.doi.org/10.1152/physiol.00025.2010.
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Eukaryotic cells are characterized by their varied complement of organelles. One set of membrane-bound, usually spherical compartments are commonly grouped together under the term peroxisomes. Peroxisomes function in regulating the synthesis and availability of many diverse lipids by harnessing the power of oxidative reactions and contribute to a number of metabolic processes essential for cellular differentiation and organismal development.
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Vogel, Rebecca. "Viral and Cellular Components of AAV2 Replication Compartments." Open Virology Journal 7, no. 1 (October 18, 2013): 98–120. http://dx.doi.org/10.2174/1874357901307010098.
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Ma, Changle, Gaurav Agrawal, and Suresh Subramani. "Peroxisome assembly: matrix and membrane protein biogenesis." Journal of Cell Biology 193, no. 1 (April 4, 2011): 7–16. http://dx.doi.org/10.1083/jcb.201010022.
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The biogenesis of peroxisomal matrix and membrane proteins is substantially different from the biogenesis of proteins of other subcellular compartments, such as mitochondria and chloroplasts, that are of endosymbiotic origin. Proteins are targeted to the peroxisome matrix through interactions between specific targeting sequences and receptor proteins, followed by protein translocation across the peroxisomal membrane. Recent advances have shed light on the nature of the peroxisomal translocon in matrix protein import and the molecular mechanisms of receptor recycling. Furthermore, the endoplasmic reticulum has been shown to play an important role in peroxisomal membrane protein biogenesis. Defining the molecular events in peroxisome assembly may enhance our understanding of the etiology of human peroxisome biogenesis disorders.
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Higgs, Martin R., Valerie G. Preston, and Nigel D. Stow. "The UL15 protein of herpes simplex virus type 1 is necessary for the localization of the UL28 and UL33 proteins to viral DNA replication centres." Journal of General Virology 89, no. 7 (July 1, 2008): 1709–15. http://dx.doi.org/10.1099/vir.0.2008/000448-0.
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The UL15, UL28 and UL33 proteins of herpes simplex virus type 1 (HSV-1) are thought to comprise a terminase complex responsible for cleavage and packaging of the viral genome into pre-assembled capsids. Immunofluorescence studies confirmed that shortly after infection with wild-type HSV-1 these three proteins localize to viral DNA replication compartments within the nucleus, identified by the presence of the single-stranded DNA-binding protein, ICP8. In cells infected with either UL28- or UL33-null mutants, the other two terminase proteins also co-localized with ICP8. In contrast, neither UL28 nor UL33 was detectable in replication compartments following infection with a UL15-null mutant, although Western blot analysis showed they were present in normal amounts in the infected cells. Provision of UL15 in a complementing cell line restored the ability of all three proteins to localize to replication compartments. These data indicate that UL15 plays a key role in localizing the terminase complex to DNA replication compartments, and that it can interact independently with UL28 and UL33.
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Reid, Colleen, Adriana Airo, and Tom Hobman. "The Virus-Host Interplay: Biogenesis of +RNA Replication Complexes." Viruses 7, no. 8 (August 6, 2015): 4385–413. http://dx.doi.org/10.3390/v7082825.
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Wellinger, Ralf E., Félix Prado, and Andrés Aguilera. "Replication Fork Progression Is Impaired by Transcription in Hyperrecombinant Yeast Cells Lacking a Functional THO Complex." Molecular and Cellular Biology 26, no. 8 (April 15, 2006): 3327–34. http://dx.doi.org/10.1128/mcb.26.8.3327-3334.2006.
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ABSTRACT THO/TREX is a conserved, eukaryotic protein complex operating at the interface between transcription and messenger ribonucleoprotein (mRNP) metabolism. THO mutations impair transcription and lead to increased transcription-associated recombination (TAR). These phenotypes are dependent on the nascent mRNA; however, the molecular mechanism by which impaired mRNP biogenesis triggers recombination in THO/TREX mutants is unknown. In this study, we provide evidence that deficient mRNP biogenesis causes slowdown or pausing of the replication fork in hpr1Δ mutants. Impaired replication appears to depend on sequence-specific features since it was observed upon activation of lacZ but not leu2 transcription. Replication fork progression could be partially restored by hammerhead ribozyme-guided self-cleavage of the nascent mRNA. Additionally, hpr1Δ increased the number of S-phase but not G2-dependent TAR events as well as the number of budded cells containing Rad52 repair foci. Our results link transcription-dependent genomic instability in THO mutants with impaired replication fork progression, suggesting a molecular basis for a connection between inefficient mRNP biogenesis and genetic instability.
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Martinez, Eric, Julie Allombert, Franck Cantet, Anissa Lakhani, Naresh Yandrapalli, Aymeric Neyret, Isobel H. Norville, Cyril Favard, Delphine Muriaux, and Matteo Bonazzi. "Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development." Proceedings of the National Academy of Sciences 113, no. 23 (May 25, 2016): E3260—E3269. http://dx.doi.org/10.1073/pnas.1522811113.
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The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome- and autophagy-derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella-containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations.
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de Oliveira, Anna Paula, Daniel L. Glauser, Andrea S. Laimbacher, Regina Strasser, Elisabeth M. Schraner, Peter Wild, Urs Ziegler, Xandra O. Breakefield, Mathias Ackermann, and Cornel Fraefel. "Live Visualization of Herpes Simplex Virus Type 1 Compartment Dynamics." Journal of Virology 82, no. 10 (March 12, 2008): 4974–90. http://dx.doi.org/10.1128/jvi.02431-07.
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ABSTRACT We have constructed a recombinant herpes simplex virus type 1 (HSV-1) that simultaneously encodes selected structural proteins from all three virion compartments—capsid, tegument, and envelope—fused with autofluorescent proteins. This triple-fluorescent recombinant, rHSV-RYC, was replication competent, albeit with delayed kinetics, incorporated the fusion proteins into all three virion compartments, and was comparable to wild-type HSV-1 at the ultrastructural level. The VP26 capsid fusion protein (monomeric red fluorescent protein [mRFP]-VP26) was first observed throughout the nucleus and later accumulated in viral replication compartments. In the course of infection, mRFP-VP26 formed small foci in the periphery of the replication compartments that expanded and coalesced over time into much larger foci. The envelope glycoprotein H (gH) fusion protein (enhanced yellow fluorescent protein [EYFP]-gH) was first observed accumulating in a vesicular pattern in the cytoplasm and was then incorporated primarily into the nuclear membrane. The VP16 tegument fusion protein (VP16-enhanced cyan fluorescent protein [ECFP]) was first observed in a diffuse nuclear pattern and then accumulated in viral replication compartments. In addition, it also formed small foci in the periphery of the replication compartments which, however, did not colocalize with the small mRFP-VP26 foci. Later, VP16-ECFP was redistributed out of the nucleus into the cytoplasm, where it accumulated in vesicular foci and in perinuclear clusters reminiscent of the Golgi apparatus. Late in infection, mRFP-VP26, EYFP-gH, and VP16-ECFP were found colocalizing in dots at the plasma membrane, possibly representing mature progeny virus. In summary, this study provides new insights into the dynamics of compartmentalization and interaction among capsid, tegument, and envelope proteins. Similar strategies can also be applied to assess other dynamic events in the virus life cycle, such as entry and trafficking.
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Nevers, Quentin, Aurélie A. Albertini, Cécile Lagaudrière-Gesbert, and Yves Gaudin. "Negri bodies and other virus membrane-less replication compartments." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1867, no. 12 (December 2020): 118831. http://dx.doi.org/10.1016/j.bbamcr.2020.118831.
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