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

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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.
Publisher
SPRINGER BASEL AG
Issue Date
2021-03
Language
English
Article Type
Article
Citation

CELLULAR AND MOLECULAR LIFE SCIENCES, v.78, no.5, pp.2315 - 2328

ISSN
1420-682X
DOI
10.1007/s00018-020-03650-4
URI
http://hdl.handle.net/10203/282229
Appears in Collection
BS-Journal Papers(저널논문)
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