ATG-3 limits Orsay virus infection in C. elegans and regulates collagen pathways

TL;DR

This study shows that ATG-3, a protein involved in autophagy, helps protect C. elegans from Orsay virus and influences collagen pathways important for antiviral defense.

Contribution

The study reveals a novel antiviral role of ATG-3 in C. elegans that is independent of its role in autophagy and connects it to collagen pathways.

Findings

ATG-3 limits Orsay virus infection at a post-entry step, independent of autophagic flux.

ATG-3 mutants show similar viral susceptibility to RNAi mutants but do not have RNAi defects.

ATG-3 influences collagen gene expression, including antiviral sqt-2, suggesting a role in antiviral collagen pathways.

Abstract

Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay virus infection of Caenorhabditis elegans. Orsay virus infection does not modulate autophagic flux, and re-feeding after starvation limits Orsay virus infection and blocks autophagic flux, suggesting that the role of ATG-3 in Orsay virus susceptibility is independent of its role in maintaining autophagic flux. atg-3 mutants phenocopy rde-1 mutants, which have a defect in RNA interference (RNAi), in susceptibility to Orsay virus infection and transcriptional response to infection. However, atg-3 mutants do not exhibit defects in RNAi. Additionally, ATG-3 limits viral infection at a post-entry step, similar to RDE-1. Differential expression analysis using RNA sequencing revealed that antiviral sqt-2, which encodes a collagen trimer protein, is depleted in mock-infected and infected atg-3 mutants, as well as in infected WT animals, as are numerous other collagen genes. These data suggest that ATG-3 may have a role in collagen organization pathways that function in antiviral defense in C. elegans.

Autophagy is an essential cellular process which functions to maintain cellular homeostasis in response to stressors such as starvation or infection through the formation of double-walled, membranous compartments called autophagosomes which engulf unwanted materials. Here, we report that a subset of autophagy factors including ATG-3, which is involved in elongation of the autophagosomal membrane, play an antiviral role in Orsay virus infection of Caenorhabditis (C.) elegans nematodes. Orsay virus is the first virus discovered to naturally infect intestinal cells in C. elegans, which makes it a valuable model system to investigate the relationship between autophagy and viral infection in a well-studied laboratory organism. We found that ATG-3 limits viral infection at a post-entry step independently from its role in maintaining autophagic flux. We performed differential expression analysis using RNA sequencing to reveal that antiviral sqt-2, which encodes a collagen trimer protein, is depleted in mock-infected and infected atg-3 mutants, as well as in infected WT animals, as are numerous other collagen genes. These findings suggest that ATG-3 may have a role in collagen organization pathways that function in antiviral defense in C. elegans.

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