title: RKIP and TBK1 form a positive feedback loop to promote type I interferon production in innate immunity.
abstract: TANK-binding kinase 1 (TBK1) activation is a central event in type I interferon production in anti-virus innate immunity. However, the regulatory mechanism underlying TBK1 activation remains unclear. Here we report that Raf kinase inhibitory protein (RKIP) is essential for TBK1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK1. Phosphorylation of RKIP enhances its interaction with TBK1 and in turn promotes TBK1 autophosphorylation. Mutation of RKIP S109 to alanine abrogates the interaction between RKIP and TBK1, 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 TBK1 that is essential for type I interferon production in anti-viral innate immunity.
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Meidi
authors.identifier: 0000-0002-7001-7911
authors.initials: M
authors.lastname: Gu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lai
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
authors.forename: Si
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China wangxiaojian@cad.zju.edu.cn.
authors.forename: Xiaojian
authors.identifier: 0000-0001-8232-0558
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D006561:Herpes Simplex / Q000276:immunology / Q000473:pathology / Q000821:virology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018353:Rhabdoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D018139:Simplexvirus / Q000276:immunology*; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D049488:Phosphatidylethanolamine Binding Protein; C539308:Raf kinase inhibitory protein, mouse; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: 
  RKIP
  ; TBK1; anti‐viral immunity; type I interferon