Autophagy machinery as exploited by viruses

Abstract

Viruses adapt and modulate cellular pathways to allow their replication in host cells. The catabolic pathway of macroautophagy, for simplicity referred to as autophagy, is no exception. In this review, we discuss anti-viral functions of both autophagy and select components of the autophagy machinery, and how viruses have evaded them. Some viruses use the membrane remodeling ability of the autophagy machinery to build their replication compartments in the cytosol or efficiently egress from cells in a non-lytic fashion. Some of the autophagy machinery components and their remodeled membranes can even be found in viral particles as envelopes or single membranes around virus packages that protect them during spreading and transmission. Therefore, studies on autophagy regulation by viral infections can reveal functions of the autophagy machinery beyond lysosomal degradation of cytosolic constituents. Furthermore, they can also pinpoint molecular interactions with which the autophagy machinery can most efficiently be manipulated, and this may be relevant to develop effective disease treatments based on autophagy modulation.

Keywords: Endosomal damage; interferon; replication organelle; secretory autophagy; virophagy.

Figure 1.

Examples of autophagy in targeting of viral entry, of sensors of viral genomes and of innate immune receptors of danger associated molecular patterns. During the cytoplasm entry by non-enveloped viruses, endosomal damage or virus capsids themselves can be recognized and targeted to degradation by autophagy. Viral DNA is detected by the CGAS-STING1 pathway, leading to type I interferon production. STING1 can also be degraded by autophagy. Damaged mitochondria activate inflammasomes triggering IL1 and IL18 production, and both are turned over by autophagy. Overall, autophagy restricts viruses during entry but at the same time dampens immune activation. ATG8, mammalian Atg8 homolog.

Figure 2.

Viruses hijack autophagosomal membranes to establish or protect their replication in the cytosol, and for envelope acquisition during egress. Positive single-stranded RNA viruses often replicate in association with membrane compartments that can be assembled with the help of the ATG machinery. Once encapsulated, the viral particles can egress in virus packages within ATG8 protein-decorated membranes. Some DNA viruses also acquire their envelope from/with autophagosomal membranes and then carry parts of the ATG machinery in their virus particles. ATG8, mammalian Atg8 homolog.