Complex Dynamic Development of Poliovirus Membranous Replication Complexes

Belov, George A.; Nair, Vinod; Hansen, Bryan; Hoyt, Forrest; Fischer, Elizabeth R.; Ehrenfeld, Ellie

doi:10.1128/jvi.05937-11

Cited by 208 publications

(318 citation statements)

References 58 publications

Supporting

Mentioning

301

Contrasting

Order By: Relevance

“…Similarly, other studies of membrane rearrangements during infection with Kunjin and West Nile virus suggest that Golgi proteins are indeed recruited to replication sites (36,47,48). Moreover, based on electron microscopy studies, it was suggested that Golgi membranes are the initial sites of poliovirus replication complexes (35). In this context our results highlight a previously unexplored role for IRGM as a Golgi protein that contributes to HCV replication.…”

Section: Discussionsupporting

confidence: 62%

“…GBF1 and Arf1, proteins that conserve Golgi maintenance and function, are known to be crucial for the replication of certain RNA viruses, such as enteroviruses (17), possibly by recruitment of PI4KIIIβ to viral replication sites. Indeed, recent data have revealed that the Golgi membrane and Golgi proteins may have a previously unappreciated role in the replication of Enterovirus and Flavivirus (35,36). Moreover, GBF1 and Arf1 have been suggested to be host factors for HCV (18)(19)(20).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hansen

Johnsen

Stiberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

127

View full text Add to dashboard Cite

Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.HCV | Golgi fragmentation | autophagy | IRGM | membranous web H epatitis C virus (HCV) is a positive-sense RNA virus in the family Flaviviridae that is a major cause of chronic liver disease. All positive-strand RNA viruses studied until now, including HCV, replicate their genomes in association with cellular membrane rearrangements. In this process, viruses remodel intracellular membranes [e.g., of mitochondria, endoplasmic reticulum (ER), and plasma membrane] to generate membrane structures such as single-or double-membrane vesicles that contribute to viral replication complexes (VRCs). HCV replication takes place at a unique subcellular compartment, the membranous web (MW), which has been proposed to be derived from the ER (1, 2). The HCV MW has a complex morphology consisting of clusters of single-, double-, and multimembrane vesicles and probably includes autophagosomes and lipid droplets (1, 3, 4). Recent findings reveal that the MW is produced by distinct HCV nonstructural (NS) proteins acting through sequential interaction with several host factors, such as the virus-targeted phosphatidylinositol-4 kinase III α (PI4KIIIα) (2, 3), but the full spectrum of host components and precise membrane composition that supports HCV replication are not fully defined.Autophagy is an evolutionarily conserved cellular mechanism that involves intracellular membrane trafficking and degradation to maintain cell homeostasis. Viruses, including HCV, have been reported to exploit autophagy for replication purposes (4-6), but the mechanism by which this exploitation occurs is largely unknown. De novo synthesis of autophagosomes is a complex process that involves the formation of a phagophore membrane and its elongation. Initiation of autophagy is regulated by the mammalian target of rapamycin complex 1 (mTORC1), which neg...

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hansen

Johnsen

Stiberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

127

View full text Add to dashboard Cite

show abstract

“…7, inset 1b). Vesicles shaped in this way have been described as appearing in chronological order in rosette-like structures observed during poliovirus infection (Belov et al, 2012). It is also unknown whether the proportion of double-membraned vesicles increases with infection and the role, if any, that they play.…”

Section: Discussionmentioning

confidence: 99%

Influenza A virus ribonucleoproteins modulate host recycling by competing with Rab11 effectors

Vale-Costa

Alenquer

Sousa

et al. 2016

Journal of Cell Science

127

View full text Add to dashboard Cite

Influenza A virus assembly is an unclear process, whereby individual virion components form an infectious particle. The segmented nature of the influenza A genome imposes a problem to assembly because it requires packaging of eight distinct RNA particles (vRNPs). It also allows genome mixing from distinct parental strains, events associated with influenza pandemic outbreaks. It is important to public health to understand how segmented genomes assemble, a process that is dependent on the transport of components to assembly sites. Previously, it has been shown that vRNPs are carried by recycling endosome vesicles, resulting in a change of Rab11 distribution. Here, we describe that vRNP binding to recycling endosomes impairs recycling endosome function, by competing for Rab11 binding with family-interacting proteins, and that there is a causal relationship between Rab11 ability to recruit family-interacting proteins and Rab11 redistribution. This competition reduces recycling sorting at an unclear step, resulting in clustering of single- and double-membraned vesicles. These morphological changes in Rab11 membranes are indicative of alterations in protein and lipid homeostasis during infection. Vesicular clustering creates hotspots of the vRNPs that need to interact to form an infectious particle.Fundação para a Ciência e Tecnologia grants: (PTDC/IMI-MIC/1142/2012, SFRH/BPD/94204/2013, SFRH/BPD/62982/2009, IF/00899/2013); Fundação Calouste Gulbenkian; Instituto Gulbenkian de Ciência

show abstract

“…These three viruses infect plants or humans and belong to the alphavirus-, flavivirius-, or picornavirus-like superfamily, respectively. They also induce very different membrane-bound VRCs: BMV forms single-membrane spherules that remain connected to the ER membrane (6), whereas HCV forms convoluted membrane webs and DMVs (double-membrane vesicles) (37) and poliovirus induces DMVs and tubular structures (38). Despite the topological differences in VRC structures, these viruses specifically promoted PC synthesis/ accumulation at the viral replication sites, suggesting a common feature shared by them and possibly by other (+)RNA viruses.…”

Section: Discussionmentioning

confidence: 99%

Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Zhang

Chukkapalli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

112

View full text Add to dashboard Cite

All positive-strand RNA viruses reorganize host intracellular membranes to assemble their viral replication complexes (VRCs); however, how these viruses modulate host lipid metabolism to accommodate such membrane proliferation and rearrangements is not well defined. We show that a significantly increased phosphatidylcholine (PC) content is associated with brome mosaic virus (BMV) replication in both natural host barley and alternate host yeast based on a lipidomic analysis. Enhanced PC levels are primarily associated with the perinuclear ER membrane, where BMV replication takes place. More specifically, BMV replication protein 1a interacts with and recruits Cho2p (choline requiring 2), a host enzyme involved in PC synthesis, to the site of viral replication. These results suggest that PC synthesized at the site of VRC assembly, not the transport of existing PC, is responsible for the enhanced accumulation. Blocking PC synthesis by deleting the CHO2 gene resulted in VRCs with wider diameters than those in wild-type cells; however, BMV replication was significantly inhibited, highlighting the critical role of PC in VRC formation and viral replication. We further show that enhanced PC levels also accumulate at the replication sites of hepatitis C virus and poliovirus, revealing a conserved feature among a group of positive-strand RNA viruses. Our work also highlights a potential broad-spectrum antiviral strategy that would disrupt PC synthesis at the sites of viral replication but would not alter cellular processes.positive-strand RNA viruses | viral replication complexes | virus-host interactions | virus control | phospholipids A ll positive-strand RNA viruses [(+)RNA viruses], which include numerous important human, animal, and plant pathogens, share similar strategies for genomic replication. A highly conserved and indispensable feature of their replication is the proliferation and reorganization of host cellular membranes to assemble viral replication complexes (VRCs). Despite this central importance, it is largely unknown how cellular membranes are rearranged by the viral replication proteins and how cellular lipid metabolism is modulated to accommodate membrane proliferation and remodeling.Brome mosaic virus (BMV) serves as a model for understanding VRC formation of (+)RNA viruses (1). BMV is the type member of the plant virus family Bromoviridae and a representative member of the alphavirus-like superfamily, which includes many human, animal, and plant-infecting viruses (2). BMV encodes two replication proteins, 1a and 2a pol . 2a pol serves as the replicase, whereas 1a has an N-terminal methyltransferase domain (3, 4) and a C-terminal ATPase/helicase-like domain (5). Together, 1a and 2a pol are necessary and sufficient for BMV replication. BMV induces vesicular structures in its surrogate host, the yeast Saccharomyces cerevisiae, and its natural host, barley (6, 7). These structures, termed spherules, have been shown to be the VRCs in yeast as 1a, 2a pol , and nascent viral RNAs reside in the interior of th...

show abstract

Complex Dynamic Development of Poliovirus Membranous Replication Complexes

Cited by 208 publications

References 58 publications

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Influenza A virus ribonucleoproteins modulate host recycling by competing with Rab11 effectors

Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Contact Info

Product

Resources

About