RKIP and TBK 1 form a positive feedback loop to promote type I interferon production in innate immunity

Abstract TANK ‐binding kinase 1 ( TBK 1) activation is a central event in type I interferon production in anti‐virus innate immunity. However, the regulatory mechanism underlying TBK 1 activation remains unclear. Here we report that Raf kinase inhibitory protein ( RKIP ) is essential for TBK 1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK 1. Phosphorylation of RKIP enhances its interaction with TBK 1 and in turn promotes TBK 1 autophosphorylation. Mutation of RKIP S109 to alanine abrogates the interaction between RKIP and TBK 1, and the anti‐viral function of RKIP . RKIP deficiency inhibits intracellular double‐stranded RNA ‐ or DNA ‐induced type I interferon production. Consistently, RKIP deficiency renders the mice more susceptible to vesicular stomatitis virus ( VSV ) and herpes simplex virus ( HSV ) infections. This study reveals a previously unrecognized positive feedback loop between RKIP and TBK 1 that is essential for type I interferon production in anti‐viral innate immunity.