Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus

Baker, S.F., Meistermann, H., Tzouros, M., Baker, A., Golling, S., Polster, J.S., Ledwith, M.P., Gitter, A., Augustin, A., Javanbakht, H., Mehle, A., 2022. Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus. PLOS Biology 20, e3001934. 

open access –

pre-print –

Viruses must balance their reliance on host cell machinery for replication while avoiding host defense. They often exploit conserved essential host genes whose critical role for the cell limits mutational escape. Conversely, host antiviral genes are often nonessential and can undergo mutation or regulated expression to thwart infection and limit self damage. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized outbreaks with the potential for larger pandemics. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Here we used immuno-competitive capturemass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. We focused on the pro-viral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the anti-viral activity of mitochondrial enoyl CoA-reductase (MECR). MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, we could not confirm interactions with full-length MECR. By contrast, RNA-seq revealed a minor splice variant that creates cytoplasmic MECR (cMECR). cMECR engages the viral polymerase and suppresses viral replication. MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block virus replication. Using the yeast homolog Etr1 to supply the metabolic functions of MECR, we showed that specific antiviral activity is independent of mtFAS and lies solely within cMECR. Thus, a cryptic antiviral activity is embedded within a key metabolic enzyme, possibly protecting it from viral countermeasures.