TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-kappa B signaling pathway in macrophages
- Authors
- Roh, Kyung-Hye; Lee, Yeojin; Yoon, Je-Hyun; Lee, Danbi; Kim, Eunju; Park, Eunchong; Lee, In Young; Kim, Tae Sung; Song, Hyun Kyu; Shin, Jaekyoon; Lim, Dae-Sik; Choi, Eui-Ju
- Issue Date
- 3월-2021
- Publisher
- SPRINGER BASEL AG
- Keywords
- Lipopolysaccharides; MST1/STK4; NF-kappa B; TRAF6
- Citation
- CELLULAR AND MOLECULAR LIFE SCIENCES, v.78, no.5, pp.2315 - 2328
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELLULAR AND MOLECULAR LIFE SCIENCES
- Volume
- 78
- Number
- 5
- Start Page
- 2315
- End Page
- 2328
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/137771
- DOI
- 10.1007/s00018-020-03650-4
- ISSN
- 1420-682X
- Abstract
- 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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