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Meta- and Orthogonal Integration of Influenza ‘OMICs’ Data Reveals UBR4 as a Critical Regulator of M2 Ion Channel Membrane Trafficking

Tripathi, Shashank, Pohl, Marie Teres, Zhou, Yingyao, Rodriguez-Frandsen, Ariel, Brass, Abe, Elledge, Steve, White, Mike, Shapira, Sagi, Hacohen, Nir, Andenmatten, Dario, Yanguez, Emilio, DeJesus, Paul, Jianwei, Che, Gatorano, Andre, Shales, Mike, Meyer, Thomas, Manicassamy, Balaji, Stein, Dave, Moulton, Hong, Shaw, Megan, Krogan, Nevan, Konig, Renate, Stertz, Sikle, Garcia-Sastre, Adolfo and Chanda, Sumit (2015) Meta- and Orthogonal Integration of Influenza ‘OMICs’ Data Reveals UBR4 as a Critical Regulator of M2 Ion Channel Membrane Trafficking. Cell host & microbe, 18 (6). pp. 723-735. ISSN 1934-6069


Systems-level analyses of the molecular interfaces between influenza A and its human host have provided considerable new insights into cellular circuits and processes that govern viral infection. However, apparent discordant results from various approaches, including RNAi screens and proteomics studies, have hampered leveraging of these findings to advance mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we have performed a meta-analysis of previously unpublished primary datasets sets from 4 siRNA screens, along with results from an additional 4 RNAi screens, to rank prioritize host and restriction factors that were found to impact viral replication in multiple datasets. This approach enabled us to identify nearly 200 published factors, as well as the 57 previously unreported host proteins, with activities supported by multiple datasets, and indicate ~50% overlap of published genes when observed at the level of cellular pathways or biochemical complexes. Further integration of these data with published and experimentally generated protein interaction data revealed the landscape of biochemical interactions between 264 host proteins found to be essential for influenza A replication and 11 virally encoded proteins. Notably, we find that the putative E3 ligase UBR4 physically associates with the virally encoded M2 protein to direct it’s trafficking to the cellular membrane. Inhibition of UBR4 results in relocalization of M2 with the autophagosomal marker ARHI and also its degradation, resulting in a severe attenuation of late phase influenza A replication. The requirement for this host protein was found to be restricted to human, but not avian, strains of the virus, suggesting that adaptations that enable the appropriation of mammalian UBR4 may be critical to zoonotic transmission and/or pathogenesis. Taken together, the integrative analysis of influenza OMICs datasets illuminate a viral-host network of high confidence human proteins that are essential for influenza A replication, and furthermore uncovers a role for UBR4 in the trafficking of the virally-encoded M2 ion channel to the cell membrane to enable viral egress.

Item Type: Article
Keywords: Influenza, RNAi Screen, Meta-Analysis
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45


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