Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production

Lassen, Susan; Grüttner, Cordula; Nguyen-Dinh, Van; Herker, Eva

doi:10.1242/jcs.217042

Cited by 17 publications

(11 citation statements)

References 79 publications

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“…In agreement with this idea, the silencing of Rab18, a lipid droplet-associated cellular protein which binds to NS5A, reduces the association of other HCV replication complex components with LDs (Salloum et al, 2013). In addition, in a recent study, a defect in PLIN2/ADRP, the major LDs coat protein in hepatocytes, restricted the LD access for HCV core and NS5A proteins and reduced intracellular infectious HCV particle formation (Lassen et al, 2019).…”

Section: Lds-involvement In Flaviviridae Life Cyclementioning

confidence: 74%

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

Fan

Zou

et al. 2021

Front. Microbiol.

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Diseases caused by Flaviviridae have a wide global and economic impact due to high morbidity and mortality. Flaviviridae infection usually leads to severe, acute or chronic diseases, such as liver injury and liver cancer resulting from hepatitis C virus (HCV) infection, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) caused by dengue virus (DENV). Given the highly complex pathogenesis of Flaviviridae infections, they are still not fully understood at present. Accumulating evidence suggests that host autophagy is disrupted to regulate the life cycle of Flaviviridae. Organelle-specific autophagy is able to selectively target different organelles for quality control, which is essential for regulating cellular homeostasis. As an important sub process of autophagy, lipophagy regulates lipid metabolism by targeting lipid droplets (LDs) and is also closely related to the infection of a variety of pathogenic microorganisms. In this review, we briefly understand the LDs interaction relationship with Flaviviridae infection, outline the molecular events of how lipophagy occurs and the related research progress on the regulatory mechanisms of lipophagy in Flaviviridae infection. Exploring the crosstalk between viral infection and lipophagy induced molecular events may provide new avenues for antiviral therapy.

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Section: Lds-involvement In Flaviviridae Life Cyclementioning

confidence: 74%

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

Fan

Zou

et al. 2021

Front. Microbiol.

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“…Diacylglycerol acyltransferase-1 localizes NS5A to LDs and promotes NS5A and core interaction (14). Perilipin-2 expression is required for trafficking of core and NS5A to LDs and for the formation of HCV particles (15). We also showed that overexpression of PACSIN2 promotes NS5A and core interaction, which facilitates HCV particle assembly (16).…”

mentioning

confidence: 69%

Cortactin Interacts with Hepatitis C Virus Core and NS5A Proteins: Implications for Virion Assembly

Nguyen

et al. 2020

J Virol

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Hepatitis C virus (HCV) exploits cellular proteins to facilitate viral propagation. To identify the cellular factors involved in HCV life cycle, we previously performed protein microarray assays using either HCV nonstructural 5A (NS5A) protein or core protein as a probe. Interestingly, cellular cortactin strongly interacted with both NS5A and core. Cortactin is an actin-binding protein critically involved in tumor progression by regulating migration and invasion of cancerous cells. Protein interaction between cortactin and NS5A or core was confirmed by coimmunoprecipitation and immunofluorescence assays. We showed that cortactin interacted with NS5A and core via N-terminal acidic domain of cortactin. Cortactin expression levels were not altered by HCV infection. siRNA-mediated knockdown of cortactin dramatically decreased HCV protein expression and infectivity levels, whereas overexpression of cortactin increased viral propagation. Ectopic expression of the siRNA-resistant cortactin recovered the viral infectivity, suggesting that cortactin was specifically required for HCV propagation. We further showed that cortactin was involved in assembly step without affecting viral entry, HCV IRES-mediated translation, and replication steps of the HCV life cycle. Of note, silencing of cortactin markedly reduced both NS5A and core protein levels on the lipid droplets (LDs) and this effect was reversed by the overexpression of cortactin. Importantly, NS5A and core promoted cell migration by activating phosphorylation of cortactin at tyrosine residue 421 and 466. Taken together, these data suggest that cortactin is not only involved in HCV assembly but also plays an important role in the cell migration. IMPORTANCE Cortactin is a cytoskeletal protein that regulates cell migration in response to a number of extracellular stimuli. The functional involvement of cortactin in virus life cycle has not yet been fully understood. The most significant finding is that cortactin strongly interacted with both HCV core and NS5A. Cortactin is involved in HCV assembly by tethering core and NS5A on the LDs with no effect on LD biogenesis. It was noteworthy that HCV NS5A and core activated cortactin by phosphorylation at tyrosine 421 and 466 to regulate cell migration. Collectively, our study shows that cortactin is a novel host factor involved in viral production and HCV-associated pathogenesis.

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“…The capsid also showed extensive localization on LDs, and quantitation of LD number showed a significant decrease in infected cells. However, studies with DENV and HCV have shown that LDs increase during infection [21,53]. It is possible that lipid metabolism is differentially regulated by JEV, which is primarily a neurotropic virus.…”

Section: Discussionmentioning

confidence: 99%

Japanese encephalitis virus capsid protein interacts with non-lipidated MAP1LC3 on replication membranes and lipid droplets

Sarkar

Sharma

Kumari

et al. 2021

Journal of General Virology

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Microtubule-associated protein 1 light chain 3 (MAP1LC3) is a protein with a well-defined function in autophagy, but still incompletely understood roles in several other autophagy-independent processess. Studies have shown MAP1LC3 is a host-dependency factor for the replication of several viruses. Japanese encephalitis virus (JEV), a neurotropic flavivirus, replicates on ER-derived membranes that are marked by autophagosome-negative non-lipidated MAP1LC3 (LC3-I). Depletion of LC3 exerts a profound inhibition on virus replication and egress. Here, we further characterize the role of LC3 in JEV replication, and through immunofluorescence and immunoprecipitation show that LC3-I interacts with the virus capsid protein in infected cells. This association was observed on capsid localized to both the replication complex and lipid droplets (LDs). JEV infection decreased the number of LDs per cell indicating a link between lipid metabolism and virus replication. This capsid-LC3 interaction was independent of the autophagy adaptor protein p62/Sequestosome 1 (SQSTM1). Further, no association of capsid was seen with the Gamma-aminobutyric acid receptor-associated protein family, suggesting that this interaction was specific for LC3. High-resolution protein-protein docking studies identified a putative LC3-interacting region in capsid, 56FTAL59, and other key residues that could mediate a direct interaction between the two proteins.

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Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production

Cited by 17 publications

References 79 publications

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

Cortactin Interacts with Hepatitis C Virus Core and NS5A Proteins: Implications for Virion Assembly

Japanese encephalitis virus capsid protein interacts with non-lipidated MAP1LC3 on replication membranes and lipid droplets

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