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

Kyung Hye Roh, Yeojin Lee, Je Hyun Yoon, Danbi Lee, Eunju Kim, Eunchong Park, In Young Lee, Tae Sung Kim, Hyun Kyu Song, Jaekyoon Shin, Dae Sik Lim, Eui Ju Choi

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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-κB 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-κB 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-κB signaling pathway during macrophage activation.

Original languageEnglish
Pages (from-to)2315-2328
Number of pages14
JournalCellular and Molecular Life Sciences
Issue number5
Publication statusPublished - 2021 Mar

Bibliographical note

Publisher Copyright:
© 2020, Springer Nature Switzerland AG.


  • Lipopolysaccharides
  • MST1/STK4
  • NF-κB
  • TRAF6

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology


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