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. Copyright 2018 The Authors