TitleRestriction factor compendium for influenza A virus reveals a mechanism for evasion of autophagy.
Publication TypeJournal Article
Year of Publication2021
AuthorsMartin-Sancho, L, Tripathi, S, Rodriguez-Frandsen, A, Pache, L, Sanchez-Aparicio, M, McGregor, MJ, Haas, KM, Swaney, DL, Nguyen, TT, Mamede, JI, Churas, C, Pratt, D, Rosenthal, SB, Riva, L, Nguyen, C, Beltran-Raygoza, N, Soonthornvacharin, S, Wang, G, Jimenez-Morales, D, De Jesus, PD, Moulton, HM, Stein, DA, Chang, MW, Benner, C, Ideker, T, Albrecht, RA, Hultquist, JF, Krogan, NJ, García-Sastre, A, Chanda, SK
JournalNat Microbiol
Date Published2021 10
KeywordsAntiviral Agents, Autophagy, GTPase-Activating Proteins, Host-Pathogen Interactions, Humans, Immune Evasion, Influenza A virus, Lysosomes, Protein Binding, rab GTP-Binding Proteins, rab7 GTP-Binding Proteins, Viral Matrix Proteins, Virus Replication

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.

Alternate JournalNat Microbiol
PubMed ID34556855
Grant ListU19 AI135972 / AI / NIAID NIH HHS / United States
HHSN272201400008C / AI / NIAID NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
K22 AI136691 / AI / NIAID NIH HHS / United States
U19 AI106754 / AI / NIAID NIH HHS / United States
U19 AI117873 / AI / NIAID NIH HHS / United States