title: The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6.
abstract: Immune responses need to be tightly controlled to avoid excessive inflammation and prevent unwanted host damage. Here we report that germinal center kinase MST4 responded dynamically to bacterial infection and acted as a negative regulator of inflammation. We found that MST4 directly interacted with and phosphorylated the adaptor TRAF6 to prevent its oligomerization and autoubiquitination. Accordingly, MST4 did not inhibit lipopolysaccharide-induced cytokine production in Traf6(-/-) embryonic fibroblasts transfected to express a mutant form of TRAF6 that cannot be phosphorylated at positions 463 and 486 (with substitution of alanine for threonine at those positions). Upon developing septic shock, mice in which MST4 was knocked down showed exacerbated inflammation and reduced survival, whereas heterozygous deletion of Traf6 (Traf6(+/-)) alleviated such deleterious effects. Our findings reveal a mechanism by which TRAF6 is regulated and highlight a role for MST4 in limiting inflammatory responses.
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Shi
authors: S
authors: Jiao
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Zhen
authors: Z
authors: Zhang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Chuanchuan
authors: C
authors: Li
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Min
authors: M
authors: Huang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Zhubing
authors: 0000000296244960
authors: Z
authors: Shi
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yanyan
authors: Y
authors: Wang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Xiaomin
authors: X
authors: Song
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Heng
authors: H
authors: Liu
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Chunyang
authors: C
authors: Li
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Min
authors: M
authors: Chen
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Wenjia
authors: W
authors: Wang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yun
authors: Y
authors: Zhao
authors: 1] State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China. [2] Peking University-Tsinghua University Joint Center for Life Sciences, Beijing, China.
authors: Zhengfan
authors: Z
authors: Jiang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Hongyan
authors: H
authors: Wang
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Catherine C L
authors: CC
authors: Wong
authors: National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Chen
authors: C
authors: Wang
authors: 1] National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2] School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors: Zhaocai
authors: Z
authors: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018805:Sepsis / Q000097:blood; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D048029:TNF Receptor-Associated Factor 6; C430908:STK26 protein, human; D000099317:Hippo Kinases
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