The interplay of autophagy and enterovirus

Abstract

Autophagy, an evolutional conserved lysosomal degradation process, has been implicated to play an important role in cellular defense against a variety of microbial infection. Interestingly, numerous studies found that some pathogens, especially positive-single-strand RNA viruses, actually hijacked autophagy machinery to promote virus infection within host cells, facilitating different stages of viral life cycle, from replication, assembly to egress. Enterovirus, a genus of positive-strand RNA virus, can cause various human diseases and is one of main public health threat globally, yet no effective clinical intervention is available for enterovirus infection. Here we summarized recent literature on how enteroviruses regulate and utilize autophagy process to facilitate their propagation in the host cells. The studies on the interplay between enterovirus and autophagy not only shed light on the molecular mechanisms underlying how enterovirus hijacks cellular components and pathway for its own benefits, but also provide therapeutic option against enterovirus infection.

Keywords: Autophagy; Enterovirus; Replication organelles.

Fig. 1

Overview of Enterovirus’ subversion of autophagy pathway. In enterovirus infections, the life cycle of enterovirus begins with recognition and binding to receptors on plasma membrane, followed by receptor-mediated endocytosis which results in virus uncoating and release of viral genome RNA (vRNA) into cytoplasm induced by pH change in endosomal compartment. The vRNA was primarily used as mRNA template to translate and synthesis viral proteins which was required for subsequent genome replication. It is reported that poliovirus utilizes ULK1 complex and CVB3 requires Vps34 complex to initiate autophagy. EV-A71, CVB3 and EV-D68 were beneficial from virus-induced formation of autophagosomes to promote viral genome replication. During late autophagy, autophagosomes fuse with lysosomes to form autolysosomes to degrade cargos engulfed by autophagosomes. However, in CVB3 and EV-D68 infection, viral protease 3C cleaves SNAP29, leading to blockage of auto-lysosome formation and autophagic flux. Poliovirus and CVB3 were capable of recruiting either proLC3 or LC3-I to replication organelles (ROs) (single-membrane or double-membrane) to promote viral replication in an autophagy-independent manner. Besides, CVB3 and EV-D68 manipulate extracellular membrane vesicles (EMVs) to promote non-lytic release of infectious progeny virions. 3-MA is an early-stage autophagy inhibitor that blocked PI3K3C/Vps34, while bafilomycin A1 is a late-stage autophagy inhibitor that inhibit fusion of autophagosome with lysosome.