Protection through vaccination and treatment with antivirals helps slow influenza virus, yet infections still cause approximately 61,000 deaths yearly in the United States during high severity seasons. Yearly, influenza virus epidemics shape public health programs worldwide. Spillover into new hosts and adaptation has led to endemic infection in mammals including humans, pigs, dogs, and horses. Migratory waterfowl are the natural host reservoir for influenza A viruses. Emerging and reemerging influenza viruses regularly surmount host barriers through adaptive mutations that allow them to interface with new host cell environments. To move from one host to the next, viruses must overcome cross-species transmission barriers by engaging divergent cellular cofactors while evading host-encoded antiviral proteins. Mitochondrial antiviral-signaling protein mCh, Liquid chromatography-tandem mass spectrometry LTM, Immunocompetitive capture-mass spectrometry IFN, Heterogenous nuclear ribonuclear protein U-like 1 ICC-MS, High-energy collision dissociation hnRNP UL1, No other authors declare a competing interest. Hoffmann-La Roche when performing this work. HM, MT, SG, JSP, AA and HJ were employees of F. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AM is an editorial board member for PLoS Biology and PLoS Pathogens. Romnes Faculty Fellow funded by the Wisconsin Alumni Research Foundation. AM is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease and an H. Uncropped images are found in S1 Raw Images.pdf.įunding: This work was supported by National Institutes of Health/National Institute for Allergy and Infectious Diseases R01AI164690 and the Greater Milwaukee Foundation Shaw Scientist Award to AM, R21AI125897 to AM and AG, a Roche Postdoctoral Fellowship RPF-353 and the National Institutes of Health/National Institute for Allergy and Infectious Diseases T32AI55397 to SFB, T32LM012413 to AB, and a National Science Foundation GRFP DGE-1747503 to MPL. A separate tab is associated with each panel in the Figures and Supporting Information. Remaining data can be found in 'Supporting Information.' Quantitative data are in the spreadsheet S1 Data.xlsx. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: RNA sequencing data can found as part of BioProject PRJNA667475. Received: OctoAccepted: NovemPublished: December 21, 2022Ĭopyright: © 2022 Baker et al. PLoS Biol 20(12):Īcademic Editor: Frank Kirchhoff, Ulm University Medical Center, GERMANY (2022) Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus. Thus, we propose a strategy where alternative splicing produces a cryptic antiviral protein that is embedded within a key metabolic enzyme.Ĭitation: Baker SF, Meistermann H, Tzouros M, Baker A, Golling S, Polster JS, et al. Using the yeast homolog Etr1 to supply the metabolic functions of MECR in MECR-null cells, we showed that specific antiviral activity is independent of mtFAS and is reconstituted by expressing cMECR. MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block to virus replication. Ectopic expression of cMECR shows that it binds the viral polymerase and suppresses viral replication by blocking assembly of viral ribonucleoprotein complexes (RNPs). By contrast, a minor splice variant produces cytoplasmic MECR (cMECR). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, PB2 did not interact with full-length MECR. MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). We focused on the proviral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the antiviral activity of mitochondrial enoyl CoA-reductase (MECR). Here we used immunocompetitive capture-mass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized outbreaks with the potential for larger pandemics. Viruses must balance their reliance on host cell machinery for replication while avoiding host defense.
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