Autophagy gene atg-3 limits Orsay virus infection in C. elegans through regulation of collagen pathways

Autophagy is an essential process which functions to maintain cellular homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy genes including atg-3 played an antiviral role in Orsay virus infection of Caenorhabditis elegans although infection itself did not modulate autophagic flux. Re-feeding after starvation limited Orsay virus infection and blocked autophagic flux, which suggested that the role of atg-3 in Orsay virus susceptibility was independent of its role in maintaining autophagic flux. Interestingly, atg-3 mutants phenocopied rde-1 mutants, which have a defect in RNA interference (RNAi), in transcriptional response to infection though atg-3 mutants did not exhibit defects in RNAi. Additionally, atg-3 limited viral infection at a post-entry step similar to rde-1 mutants. Differential expression analysis using RNA sequencing revealed that sqt-2, which encodes a collagen trimer protein, was depleted in infected WT animals and in naïve and infected atg-3 mutants, suggesting that atg-3 has a role in collagen organization pathways that play a role in antiviral defense in C. elegans.

细胞自噬（Autophagy）是一类维持细胞稳态的核心生理过程，可响应饥饿、感染等应激原发挥功能。本研究报道，在秀丽隐杆线虫（Caenorhabditis elegans）感染奥赛病毒（Orsay virus）的模型中，包括atg-3在内的部分自噬相关基因发挥了抗病毒作用，尽管病毒感染本身并未改变自噬流（autophagic flux）水平。饥饿后重新喂食可抑制奥赛病毒感染并阻断自噬流，这一现象提示atg-3在奥赛病毒易感性中的功能，与其维持自噬流的作用相互独立。有趣的是，尽管atg-3突变体并未表现出RNA干扰（RNA interference, RNAi）缺陷，但其感染后的转录应答表型与存在RNA干扰缺陷的rde-1突变体一致。此外，atg-3可在病毒入侵后的阶段限制病毒感染，这一表型同样与rde-1突变体相似。通过RNA测序（RNA sequencing）开展的差异表达分析显示，编码胶原三聚体蛋白的sqt-2在感染的野生型动物以及未感染和感染的atg-3突变体中均出现表达下调，这表明atg-3参与调控胶原组织通路，而该通路在秀丽隐杆线虫的抗病毒防御中发挥重要作用。