Abstract
Many viruses interface with the autophagy pathway, a highly conserved process for recycling cellular components. For three viral infections in which autophagy constituents are proviral (poliovirus, dengue, and Zika), we developed a panel of knockouts (KOs) of autophagy-related genes to test which components of the canonical pathway are utilized. We discovered that each virus uses a distinct set of initiation components; however, all three viruses utilize autophagy-related gene 9 (ATG9), a lipid scavenging protein, and LC3 (light-chain 3), which is involved in membrane curvature. These results show that viruses use noncanonical routes for membrane sculpting and LC3 recruitment. By measuring viral RNA abundance, we also found that poliovirus utilizes these autophagy components for intracellular growth, while dengue and Zika virus only use autophagy components for post-RNA replication processes. Comparing how RNA viruses manipulate the autophagy pathway reveals new noncanonical autophagy routes, explains the exacerbation of disease by starvation, and uncovers common targets for antiviral drugs.
Highlights
Manipulation of the autophagy pathway is a burgeoning field of research, providing many potential targets for antiviral, anticancer, and neuro-preservation therapies
We developed a panel of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) knockout (KO) human cells lacking individual components of the autophagy pathway to assess what aspects of the pathway diverse RNA viruses utilized
We found that PV, dengue virus (DENV), and Zika virus (ZIKV) all utilize multiple components of the autophagy pathway while bypassing others and that each virus uses a unique set of initiation components
Summary
Manipulation of the autophagy pathway is a burgeoning field of research, providing many potential targets for antiviral, anticancer, and neuro-preservation therapies. Canonical autophagy (“self-eating”) proceeds through a series of distinct steps that nucleate and expand membranous structures, termed autophagosomes, that enclose cytoplasmic contents [1] (Fig 1A). The resulting double-membraned vesicles (DMVs) fuse with lysosomes, in which hydrolases promote degradation of the cytoplasmic contents for reuse by the cell. The autophagy pathway utilizes large amount of lipids to accomplish the formation of autophagosomes. The origins of these membranes are debated but are likely to derive both from the endoplasmic reticulum (ER) and lipids scavenged from a variety of membranes throughout the cell [2,3,4,5,6]
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