Interplay between the cellular autophagy machinery and positive-stranded RNA viruses

Abstract

Autophagy is a conserved cellular process that acts as a key regulator in maintaining cellular homeostasis. Recent studies implicate an important role for autophagy in infection and immunity by removing invading pathogens and through modulating innate and adaptive immune responses. However, several pathogens, notably some positive-stranded RNA viruses, have subverted autophagy to their own ends. In this review, we summarize the current understanding of how viruses with a positive-stranded RNA genome interact with the host autophagy machinery to control their replication and spread. We review the mechanisms underlying the induction of autophagy and discuss the pro- and anti-viral functions of autophagy and the potential mechanisms involved.

Figure 1

The activation of autophagy pathway by different positive-stranded RNA viruses The process of autophagy consists of four steps: induction, nucleation, elongation, and fusion with lysosomes. Two ubiquitination-like conjugation systems, Atg12–Atg5 and LC3-PE, are essential for the formation of autophagosomes. Positive-stranded RNA viruses induce either complete or incomplete autophagy as indicated. ER stress-induced UPR, eIF2α phosphorylation, and mTOR/p70S6K signaling pathway have been associated with the activation of autophagy in HCV, EV71, and CVB3 infection, respectively. Calpain pathway is required for the activation of autophagy in CVB4 infection. ER, endoplasmic reticulum; UPR, unfolded protein response; eIF2α, eukaryotic initiation factor 2α; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal protein S6 kinase; PE, phosphatidylethanolamine; PV, poliovirus; CVB, coxsackievirus; HRV, human rhinovirus; EV71, enterovirus 71; EMCV, encephalomyocarditis virus; FMDV, foot and mouth disease virus; ChikV, chikungunya virus; SARS-CoV, severe acute respiratory syndrome-coronavirus; MHV, mouse hepatitis virus; IBV, infectious bronchitis virus; EAV, equine arteritis virus; DENV, dengue virus; JEV, Japanese encephalitis virus; SIN, sindbis virus; HCV, hepatitis C virus; ?, implicated by indirect experimental evidence but direct evidence is still missing.

Figure 2

The pro-viral and anti-viral functions of autophagy during positive-stranded RNA viral infection Pro-viral functions of autophagy (viruses are circled in black rectangles): (1) autophagosomes (PV, EV71, CVB3, EMCV, FMDV, ChikV) or amphisomes (DENV) serve as sites for viral replication; (2) amphisomes are also linked to the entry/uncoating of JEV and DENV; (3) the topological structure of autophagosmes is associated with non-lytic egress of PV particles; (4) autophagy prevents premature cell death to maintain favorable cellular environment for viral replication (DENV-2, HCV, and CVB4); (5) autophagy favors DENV replication by selectively degrading lipid droplets to generate ATP for viral replication; (6) suppression of IFN signaling is related to the pro-viral function of autophagy in HCV infection. Anti-viral functions of autophagy (viruses are circled in red rectangles): (1) autophagy inhibits SIN replication by promoting the clearance of viral capsid protein; (2) autophagy is required for TLR3-medicated type-I IFN production during CVB3 infection. PV, poliovirus; CVB, coxsackievirus; EV71, enterovirus 71; FMDV, foot and mouth disease virus; ChikV, chikungunya virus; HCV, hepatitis C virus; HRV, human rhinovirus; EMCV, encephalomyocarditis virus; SIN, sindbis virus; DENV, dengue virus; MHV, mouse hepatitis virus; JEV, Japanese encephalitis virus; FAA, free fatty acid; IFN, interferon; TLR3, toll-like receptor 3; ATP, adenosine triphosphate; ?, implicated by indirect experimental evidence but direct evidence is still missing.