Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS Biol. 2019 Jan 4;17(1):e2006926. doi: 10.1371/journal.pbio.2006926. eCollection 2019 Jan.
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.
许多病毒与自噬途径相互作用，自噬途径是一种高度保守的回收细胞成分的过程。对于三种自噬成分具有促进病毒作用的病毒感染（脊髓灰质炎病毒、登革热病毒和寨卡病毒），我们开发了一组自噬相关基因敲除（KO），以测试经典途径中的哪些成分被利用。我们发现每种病毒都使用一组独特的起始成分；然而，这三种病毒都利用自噬相关基因 9（ATG9）和 LC3（轻链 3），这两种成分参与膜曲率。这些结果表明，病毒使用非典型途径进行膜塑造和 LC3 募集。通过测量病毒 RNA 的丰度，我们还发现脊髓灰质炎病毒利用这些自噬成分进行细胞内生长，而登革热病毒和寨卡病毒仅在 RNA 复制后过程中利用自噬成分。比较 RNA 病毒如何操纵自噬途径揭示了新的非典型自噬途径，解释了饥饿对疾病的加重，并揭示了抗病毒药物的共同靶点。
