Viruses and the autophagy pathway

Abstract

Studies of the cellular autophagy pathway have exploded over the past twenty years. Now appreciated as a constitutive degradative mechanism that promotes cellular homeostasis, autophagy is also required for a variety of developmental processes, cellular stress responses, and immune pathways. Autophagy certainly acts as both an anti-viral and pro-viral pathway, and the roles of autophagy depend on the virus, the cell type, and the cellular environment. The goal of this review is to summarize, in brief, what we know so far about the relationship between autophagy and viruses, particularly for those who are not familiar with the field. With a massive amount of relevant published data, it is simply not possible to be comprehensive, or to provide a complete "parade of viruses", and apologies are offered to researchers whose work is not described herein. Rather, this review is organized around general themes regarding the relationship between autophagy and animal viruses.

Keywords: AWOL; Amphisome; Autophagy; Beclin 1; Endosome; IFN; SNARE; Virus.

Figure 1. Viral regulation of the autophagic pathway

Autophagy is initiated when a signal is sent, through the Beclin 1 complex and other signaling complexes, to convert the cellular LC3 protein from its non-lipidated LC3-I form to phosphotidylamine-conjugated LC3-II. The newly lipidated LC3-II localizes to cup-shaped Pre-Autophagosomal Structures (PAS), and is required for the PAS to self-fuse into double-membraned autophagosomes with cytosolic contents. Autophagosomes fuse with endosomes, which provide vacuolar ATPases and promote acidification of the newly formed vesicle, termed an amphisome. Acidic amphisomes fuse with lysosomes, delivering proteases for degradation of internal contents. LC3-II is recycled to LC3-I, so it is difficult to monitor flux through the pathway using LC3 lipidation. The autophagic cargo adapter p62/SQSTM1 directly interacts with LC3, which directs its localization to PAS. LC3-I and LC3-II can be distinguished by western blot, but the recycling pathway makes it difficult to use LC3-II levels to monitor autophagy. However, lower steady state levels of p62 indicate higher levels of active autophagic degradation. Many of the known virus-encoded activators of autophagic signaling, and in some cases active autophagy, are listed, although the mechanisms of activation are poorly understood. Many other viruses induce autophagic signaling, but the specific proteins which provide the signal are unknown. Several viruses are known to inhibit either autophagic signaling, or autophagic maturation, as shown. HSV-1 US11 protein inhibits autophagic signaling through inhibition of PKR. HSV-1 ICP34.5, KSHV orf16, and MHV-68 M11 inhibit autophagosome formation by binding to the Beclin 1 autophagy signaling molecule. Influenza A, CVB3, HPIV3, and EBV induce autophagosomes, but block autophagosome maturation and autophagic degradation. Influenza M2 protein binds to LC3 to inhibit amphisome formation. The HPIV3-encoded P protein binds to SNAP29, inhibiting endosome-autophagsome fusion. In the case of CVB3, the virus requires host BPIFB3 to inhibit vesicle maturation.