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

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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-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.

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Acknowledgements

We thank S. Yonehara, S. Kang, and D. Goeddel for Flag-MST1/STK4, HA-ubiquitin, and TRAF6 cDNAs, respectively, as well as V. M. Dixit for the antibody to K63-linked polyubiquitin and T. Kinashi for MST1/STK4fl/fl mice. This work was supported by a National Research Foundation grant (NRF-2020R1A2C2011392) funded by the Ministry of Science and ICT of Korea as well as by a Korea University grant (E.-J.C.). K.-H.R. was supported financially by a Global Ph.D. fellowship (2016H1A2A1907478) funded by the Ministry of Science and ICT of Korea.

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  1. Department of Life Sciences, Korea University, Seoul, 02841, Korea

    Kyung-Hye Roh, Yeojin Lee, Danbi Lee, Eunju Kim, Eunchong Park, In Young Lee, Tae Sung Kim, Hyun Kyu Song & Eui-Ju Choi

  2. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Je-Hyun Yoon

  3. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea

    Jaekyoon Shin

  4. Department of Biological Sciences, National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea

    Dae-Sik Lim

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KHR, YL, IYL, DL, EK, EP, and JHY conducted the experiments. KHR, YL, EP, TSK, HKS, JHY and EJC designed the experiments. DSL and JS provided materials. KHR and EJC wrote the paper.

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Correspondence to Eui-Ju Choi.

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Roh, KH., Lee, Y., Yoon, JH. et al. TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages. Cell. Mol. Life Sci. 78, 2315–2328 (2021). https://doi.org/10.1007/s00018-020-03650-4

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