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Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy

Martin-Sancho, L and Tripathi, S and Rodriguez-Frandsen, A and Pache, L and Sanchez-Aparicio, M and McGregor, MJ and Haas, KM and Swaney, DL and Nguyen, TT and Mamede, JI and Churas, C and Pratt, D and Rosenthal, SB and Riva, L and Nguyen, C and Beltran-Raygoza, N and Soonthornvacharin, S and Wang, G and Jimenez-Morales, D and De Jesus, PD and Moulton, HM and Stein, DA and Chang, MW and Benner, C and Ideker, T and Albrecht, RA and Hultquist, JF and Krogan, NJ and García-Sastre, A and Chanda, SK (2021) Restriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy. In: Nature Microbiology, 6 (10). pp. 1319-1333.

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Official URL: https://doi.org/10.1038/s41564-021-00964-2


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.

Item Type: Journal Article
Publication: Nature Microbiology
Publisher: Nature Research
Additional Information: The copyright for this article belongs to the Author.
Keywords: Rab7 protein; antivirus agent; guanosine triphosphatase activating protein; M2 protein, Influenza A virus; matrix protein; protein binding; Rab protein; Rab7 protein; TBC1D5 protein, human, Article; autophagosome; autophagy (cellular); controlled study; gene function; gene loss; immune evasion; in vitro study; in vivo study; Influenza A virus; lysosome; nonhuman; protein binding; protein degradation; protein interaction; protein targeting; proteomics; transcriptomics; virus replication; autophagy; genetics; host pathogen interaction; human; metabolism; pathogenicity; physiology, Antiviral Agents; Autophagy; GTPase-Activating Proteins; Host-Pathogen Interactions; Humans; Immune Evasion; Influenza A virus; Lysosomes; Protein Binding; rab GTP-Binding Proteins; Viral Matrix Proteins; Virus Replication
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Division of Biological Sciences > Centre for Infectious Disease Research
Date Deposited: 28 Jul 2023 09:48
Last Modified: 28 Jul 2023 09:48
URI: https://eprints.iisc.ac.in/id/eprint/82692

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