Enteroviruses Remodel Autophagic Trafficking through Regulation of Host SNARE Proteins to Promote Virus Replication and Cell Exit

Abstract

Enterovirus D68 (EV-D68) is a medically important respiratory plus-strand RNA virus of children that has been linked to acute flaccid myelitis. We have determined that EV-D68 induces autophagic signaling and membrane formation. Autophagy, a homeostatic degradative process that breaks down protein aggregates and damaged organelles, promotes replication of multiple plus-strand viruses. Induction of autophagic signals promotes EV-D68 replication, but the virus inhibits the downstream degradative steps of autophagy in multiple ways. EV-D68 proteases cleave a major autophagic cargo adaptor and the autophagic SNARE SNAP29, which reportedly regulates fusion between autophagosome to amphisome/autolysosome. Although the virus inhibits autophagic degradation, SNAP29 promotes virus replication early in infection. An orphan SNARE, SNAP47, is shown to have a previously unknown role in autophagy, and SNAP47 promotes the replication of EV-D68. Our study illuminates a mechanism for subversion of autophagic flux and redirection of the autophagic membranes to benefit EV-D68 replication. Enterovirus D68, a medically important respiratory virus, benefits from signaling to the host degradation pathway of autophagy. Corona et al. show that EV-D68 disrupts autophagic degradation in multiple ways, including manipulation of cellular SNAREs, to promote replication and dissemination. This suggests that redirected autophagy promotes exit of virus from cells.