Reovirus µ2 residue 208 drives SRSF2-dependent nuclear hyperaccumulation of IRF9.

Mammalian reovirus µ2 antagonizes type I interferon (IFN) signaling and is associated with nuclear hyperaccumulation of IRF9. We tested whether µ2 residue 208, which determines strain-specific IFN-β repression and modulation of host cell mRNA splicing, also controls IRF9 relocalization and whether the splicing factor SRSF2 is required. Recombinant and mutant viruses showed that T1L-like Pro208 is required and sufficient for IRF9 nuclear accumulation in L929 cells. In addition, SRSF2 depletion reduced IFN-mediated induction of Irf7 and Stat1 , but not Isg56/Ifit1 , and abolished T3D-S208P-induced IRF9 nuclear accumulation. Thus, reovirus-induced IRF9 relocalization requires both µ2 residue 208 and host SRSF2.