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Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy
Nature Microbiology ( IF 20.5 ) Pub Date : 2021-09-23 , DOI: 10.1038/s41564-021-00964-2
Laura Martin-Sancho 1 , Shashank Tripathi 2, 3, 4 , Ariel Rodriguez-Frandsen 1 , Lars Pache 1 , Maite Sanchez-Aparicio 2, 3 , Michael J McGregor 5, 6, 7 , Kelsey M Haas 5, 6, 7 , Danielle L Swaney 5, 6, 7 , Thong T Nguyen 5, 6, 7 , João I Mamede 8 , Christopher Churas 9 , Dexter Pratt 9 , Sara B Rosenthal 9 , Laura Riva 1 , Courtney Nguyen 1 , Nish Beltran-Raygoza 1 , Stephen Soonthornvacharin 1 , Guojun Wang 2, 3 , David Jimenez-Morales 5, 6, 7, 10 , Paul D De Jesus 1 , Hong M Moulton 11 , David A Stein 11 , Max W Chang 9 , Chris Benner 9 , Trey Ideker 9, 12 , Randy A Albrecht 2, 3 , Judd F Hultquist 6, 13 , Nevan J Krogan 5, 6, 7 , Adolfo García-Sastre 2, 3, 14, 15 , Sumit K Chanda 1
Affiliation  

The fate of influenza A virus (IAV) infection in the host cell depends on the balance between cellular defence mechanisms and viral evasion strategies. To illuminate the landscape of IAV cellular restriction, we generated and integrated global genetic loss-of-function screens with transcriptomics and proteomics data. Our multi-omics analysis revealed a subset of both IFN-dependent and independent cellular defence mechanisms that inhibit IAV replication. Amongst these, the autophagy regulator TBC1 domain family member 5 (TBC1D5), which binds Rab7 to enable fusion of autophagosomes and lysosomes, was found to control IAV replication in vitro and in vivo and to promote lysosomal targeting of IAV M2 protein. Notably, IAV M2 was observed to abrogate TBC1D5–Rab7 binding through a physical interaction with TBC1D5 via its cytoplasmic tail. Our results provide evidence for the molecular mechanism utilised by IAV M2 protein to escape lysosomal degradation and traffic to the cell membrane, where it supports IAV budding and growth.



中文翻译:

甲型流感病毒的限制因子纲要揭示了逃避自噬的机制

甲型流感病毒(IAV)感染宿主细胞的命运取决于细胞防御机制和病毒逃避策略之间的平衡。为了阐明 IAV 细胞限制的情况,我们生成了全球遗传功能丧失筛查,并将其与转录组学和蛋白质组学数据整合。我们的多组学分析揭示了抑制 IAV 复制的 IFN 依赖性和独立细胞防御机制的子集。其中,自噬调节因子TBC1结构域家族成员5(TBC1D5)与Rab7结合以实现自噬体和溶酶体的融合,被发现可以控制IAV在体外和体内的复制,并促进IAV M2蛋白的溶酶体靶向。值得注意的是,观察到 IAV M2 通过其胞质尾部与 TBC1D5 发生物理相互作用,从而消除了 TBC1D5-Rab7 的结合。我们的结果为 IAV M2 蛋白利用分子机制逃避溶酶体降解和运输到细胞膜提供了证据,在细胞膜上它支持 IAV 出芽和生长。

更新日期:2021-09-23
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