Subversion of Cellular Autophagosomal Machinery by RNA Viruses

By W. Jackson, T. Giddings, Matthew P. Taylor, Sara B. Mulinyawe, M. Rabinovitch, R. Kopito, K. Kirkegaard. PLoS Biology, 2005

855 citations recorded by the source corpus.

Infection of human cells with poliovirus induces the proliferation of double-membraned cytoplasmic vesicles whose surfaces are used as the sites of viral RNA replication and whose origin is unknown. Here, we show that several hallmarks of cellular autophagosomes can be identified in poliovirus-induced vesicles, including colocalization of LAMP1 and LC3, the human homolog of Saccharomyces cerevisiae Atg8p, and staining with the fluorophore monodansylcadaverine followed by fixation. Colocalization of LC3 and LAMP1 was observed early in the poliovirus replicative cycle, in cells infected with rhinoviruses 2 and 14, and in cells that express poliovirus proteins 2BC and 3A, known to be sufficient to induce double-membraned vesicles. Stimulation of autophagy increased poliovirus yield, and inhibition of the autophagosomal pathway by 3-methyladenine or by RNA interference against mRNAs that encode two different proteins known to be required for autophagy decreased poliovirus yield. We propose that, for poliovirus and rhinovirus, components of the cellular machinery of autophagosome formation are subverted to promote viral replication. Although autophagy can serve in the innate immune response to microorganisms, our findings are inconsistent with a role for the induced autophagosome-like structures in clearance of poliovirus. Instead, we argue that these double-membraned structures provide membranous supports for viral RNA replication complexes, possibly enabling the nonlytic release of cytoplasmic contents, including progeny virions, from infected cells.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology

View Paper: https://www.semanticscholar.org/paper/d617306cda56236d02117ae7a5fc5e7fcd015554

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In Cardiology and Cardiovascular Medicine

1. R. Randall
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1. Ralph A. Nixon
2. Beth Levine
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Citations in the corpus

• Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. (2008, background): “In contrast, it has been suggested that some RNA viruses may activate components of the autophagic machinery both to promote their replication on cellular membranes (Prentice et al., 2004; Jackson et al., 2005) and to limit IFN production (Jounai et al.”
• Unveiling the roles of autophagy in innate and adaptive immunity (2007, background): “The best-studied examples are the mammalian picornavirus poliovirus and the murine coronavirus mouse hepatitis virus 56, 57 .”
• Autophagy during viral infection — a double-edged sword (2018, background): “Indeed, ATG-silencing inhibited the non-lytic spread of poliovirus 125 , and autophagic membranes have similar functions for the release of other picornaviruses 79, 83 .”
• Fat(al) attraction: Picornaviruses Usurp Lipid Transfer at Membrane Contact Sites to Create Replication Organelles (2016, result): “Importantly, LC3 has been implicated in DMV formation both in an autophagy-dependent Box 1.”
• The Molecular Biology of Coronaviruses (2006, background): “Coronavirus RNA synthesis may thus take place in structures that are similar to the autophagosomal RNA synthesis compartments that have been characterized in picornavirusinfected cells (Jackson et al., 2005).”
• Autophagy, Immunity, and Microbial Adaptations (2009, background): “…of LC3-positive double membranes Proposed mechanism for nonlytic virus egress Poliovirus 2BC and 3 proteins induce GFP-LC3 colocalization with LAMP1 Jackson et al., 2005; Taylor and Kirkegaard, 2007 Coxsackievirus B3, B4 (CVB3, CVB4) CVB3 infection induces early but not late stages of autophagy;…”
• Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis (2018, neutral): “…and mCh-Rab7A were gifts from Gia Voeltz (Addgene #49150, #49151, #49152, #61804) 10,33 , EGFP-LC3 was a gift from Karla Kirkegaard (Addgene #11546) 34 , pMXs-puro GFP-DFCP1 was a gift from Noboru Mizushima (Addgene #38269) 35 , pAc-GFPC1-Sec61beta was a gift from Tom Rapoport (Addgene #15108),…”
• SARS-Coronavirus Replication Is Supported by a Reticulovesicular Network of Modified Endoplasmic Reticulum (2008, background): “Other studies revealed that poliovirus-induced vesicles may have a double membrane [63] and implicated the autophagic pathway in their formation [64].”
• PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “Although autophagy serves as a potent cellular strategy to clear pathogens, several viruses have evolved to exploit autophagic signaling to promote their replication, including dengue virus (96), hepatitis C virus (127), and poliovirus (128), among others.”
• Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease (2005, background): “, 2005), or from the direct fusion of AVs with the plasma membrane (Jackson et al., 2005).”
• Virus Entry: Open Sesame (2006, neutral): “Others may subvert cellular autophagy pathways to gain access to exocytic organelles (Jackson et al., 2005).”
• Modification of intracellular membrane structures for virus replication (2008, background): “However, small-interfering-RNA (siRNA)mediated knockout of lC3 and Atg12, an Atg that forms a complex with Atg5, inhibited the release of infectious virus without significantly affecting replication 97 .”
• Dengue virus induced autophagy regulates lipid metabolism (2010, background): “Further, markers of poliovirus replication and autophagosomes colocalize in infected cells, which has led to the hypothesis that polio virus replication structures may be at least in part derived from autophagosomes (Jackson et al., 2005).”