Cytosolic nucleic acid sensing triggers type I interferon activation via the Hippo kinase LATS1

Innate immune detection of viral genomes via nucleic acid-sensing pattern recognition receptors in the cytosolic compartment triggers the production of type I interferons (IFN-I) to coordinate a cellular antiviral state to limit viral replication and spread. While IFN-I induction is controlled primarily by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation via the virus-activated kinase, TBK1, the mechanisms underlying how TBK1 signaling is achieved remain incompletely understood. Here, we report that viral infection or cytosolic delivery of nucleic acids elicits the activation of a primordial Hippo signaling pathway that is known to control organ size and tissue homeostasis. We identify the Hippo core component, LATS1 kinase to necessitate TBK1 dependent signaling as cells treated with a pharmacological inhibitor of LATS1 or cells from Lats1^-/- mice displayed impaired TBK1-IRF3 signal activities and defective IFN-I induction upon cytosolic nucleic acid stimulation. Consequently, LATS1-deficient cells harbored elevated viral titers in comparison to WT control cells. Mechanistically, LATS1 associated with TBK1 upon cytosolic nucleic acid stimulation and promoted TBK1 signaling and activation in a kinase-dependent manner. Altogether, our findings reveal that cytosolic nucleic acid-sensing pathways elicit Hippo/LATS1 activation to govern TBK1 signaling events to result in IFN-I activation.