TY - JOUR T1 - IWS1 phosphorylation by AKT3 controls nuclear export of type I IFN mRNAs and sensitivity to oncolytic viral infection, by regulating the alternative RNA splicing of <em>U2AF2</em> JF - bioRxiv DO - 10.1101/2020.12.26.424461 SP - 2020.12.26.424461 AU - Georgios I. Laliotis AU - Adam D. Kenney AU - Evangelia Chavdoula AU - Arturo Orlacchio AU - Abdul Kaba AU - Alessandro La Ferlita AU - Vollter Anastas AU - Christos Tsatsanis AU - Joal D. Beane AU - Lalit Sehgal AU - Vincenzo Coppola AU - Jacob S. Yount AU - Philip N. Tsichlis Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/08/12/2020.12.26.424461.abstract N2 - AKT-phosphorylated IWS1 promotes Histone H3K36 trimethylation and alternative RNA splicing of target genes, including the U2AF65 splicing factor-encoding U2AF2. The predominant U2AF2 transcript, upon IWS1 phosphorylation block, lacks the RS-domain-encoding exon 2, and encodes a protein which fails to bind Prp19. Here we show that although both U2AF65 isoforms bind intronless mRNAs containing cytoplasmic accumulation region elements (CAR-E), only the RS domain-containing U2AF65 recruits Prp19 and promotes their nuclear export. The loading of U2AF65 to CAR-Elements was RS domain-independent, but RNA PolII-dependent. Virus- or poly(I:C)-induced type I IFNs are encoded by genes targeted by the pathway. IWS1 phosphorylation-deficient cells therefore, express reduced levels of IFNα1/IFNβ1 proteins, and exhibit enhanced sensitivity to infection by multiple cytolytic viruses. Enhanced sensitivity of IWS1-deficient cells to Vesicular Stomatitis Virus and Reovirus resulted in enhanced apoptotic cell death via caspase activation. Inhibition of this pathway may therefore sensitize cancer cells to oncolytic viruses.Competing Interest StatementThe authors have declared no competing interest. ER -