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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.
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页码:2315 / 2328
页数:14
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