Pivotal role for the non-receptor tyrosine kinase SRMS in IRF3-dependent innate antiviral immune response in murine cells

Abstract Upon viral infections, RIG-I-like receptors (RLRs) sense cytosolic RNAs and initiate signaling pathways culminating in the activation of IRF3 subsequent type I interferon (IFN) antiviral response. This intrinsic protective mechanism is orchestrated by a host positive negative regulators, which collectively govern magnitude duration signaling. SRMS an understudied non-receptor tyrosine kinase frequently overexpressed breast cancers. restrains autophagy promotes tumor growth, although its physiological function unclear. We report here that critical for IRF3-dependent innate response murine cells. Depletion impaired virus- or dsRNA-induced expression III IFNs ISGs mouse embryonic fibroblasts (MEFs), hepatoma hepa1–6 cells, primary lung fibroblasts, concomitant with heightened replication. Mechanistically, loss led to diminished phosphorylations TBK1 IRF3, dimerization nuclear translocation. The activity SRMS, however, was dispensable. Reconstituting human origin, be it wild-type kinase-dead protein, SRMS-null MEFs restored Autophagy regulation not involved, either. Interestingly, gene via RLRs U2OS MDA-MB-231 cells impacted deletion, suggesting redundancy Altogether, our data uncover novel role controlling responses describe non-canonical, kinase- autophagy-independent regulatory operates differentially between species. R21 AI142044