TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages

被引:10
作者
Roh, Kyung-Hye [1 ]
Lee, Yeojin [1 ]
Yoon, Je-Hyun [2 ]
Lee, Danbi [1 ]
Kim, Eunju [1 ]
Park, Eunchong [1 ]
Lee, In Young [1 ]
Kim, Tae Sung [1 ]
Song, Hyun Kyu [1 ]
Shin, Jaekyoon [3 ]
Lim, Dae-Sik [4 ]
Choi, Eui-Ju [1 ]
机构
[1] Korea Univ, Dept Life Sci, Seoul 02841, South Korea
[2] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
[3] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Dept Mol Cell Biol, Suwon 16419, South Korea
[4] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Natl Creat Res Initiat Ctr, Dept Biol Sci,Biomed Res Ctr, Daejeon 305701, South Korea
基金
新加坡国家研究基金会;
关键词
Lipopolysaccharides; MST1/STK4; NF-kappa B; TRAF6; NF-KAPPA-B; INTERACTING PROTEIN P62; NEGATIVE REGULATION; IMPORTANT MEDIATOR; MST1; KINASE; ADAPTER P62; ACTIVATION; RECEPTOR; TRAF6; IDENTIFICATION;
D O I
10.1007/s00018-020-03650-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-kappa B signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-kappa B activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-kappa B signaling pathway during macrophage activation.
引用
收藏
页码:2315 / 2328
页数:14
相关论文
共 59 条
[1]   Limiting inflammation-the negative regulation of NF-κB and the NLRP3 inflammasome [J].
Afonina, Inna S. ;
Zhong, Zhenyu ;
Karin, Michael ;
Beyaert, Rudi .
NATURE IMMUNOLOGY, 2017, 18 (08) :861-869
[2]   Biochemical analysis of MST1 kinase: Elucidation of a C-terminal regulatory region [J].
Anand, Ruchi ;
Kim, Ah-Young ;
Brent, Michael ;
Marmorstein, Ronen .
BIOCHEMISTRY, 2008, 47 (25) :6719-6726
[3]   Innate immune sensing and its roots: the story of endotoxin [J].
Beutler, B ;
Rietschel, ET .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (02) :169-176
[4]   Salmonella-induced inflammasome activation in humans [J].
Bierschenk, Damien ;
Boucher, Dave ;
Schroder, Kate .
MOLECULAR IMMUNOLOGY, 2017, 86 :38-43
[5]   MyD88, an adapter protein involved in interleukin-1 signaling [J].
Burns, K ;
Martinon, F ;
Esslinger, C ;
Pahl, H ;
Schneider, P ;
Bodmer, JL ;
Di Marco, F ;
French, L ;
Tschopp, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (20) :12203-12209
[6]   TARF6 is a signal transducer for interleukin-1 [J].
Cao, ZD ;
Xiong, J ;
Takeuchi, M ;
Kurama, T ;
Goeddel, DV .
NATURE, 1996, 383 (6599) :443-446
[7]   Toll-like receptors in the pathogenesis of human disease [J].
Cook, DN ;
Pisetsky, DS ;
Schwartz, DA .
NATURE IMMUNOLOGY, 2004, 5 (10) :975-979
[8]   The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain [J].
Creasy, CL ;
Ambrose, DM ;
Chernoff, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (35) :21049-21053
[9]   CLONING AND CHARACTERIZATION OF A HUMAN PROTEIN-KINASE WITH HOMOLOGY TO STE20 [J].
CREASY, CL ;
CHERNOFF, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (37) :21695-21700
[10]   The Ste20 group kinases as regulators of MAP kinase cascades [J].
Dan, I ;
Watanabe, NM ;
Kusumi, A .
TRENDS IN CELL BIOLOGY, 2001, 11 (05) :220-230