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Mol Cell. 2019 Mar 21;73(6):1138-1149.e6. doi: 10.1016/j.molcel.2019.01.022. Epub 2019 Feb 21.

MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity.

Author information

1
Department of Life Sciences, Korea University, Seoul 02841, South Korea.
2
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
3
Genomic Instability Research Center (GIRC), Ajou University School of Medicine, Suwon 16499, South Korea.
4
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
5
Department of Life Sciences, Korea University, Seoul 02841, South Korea. Electronic address: ejchoi@korea.ac.kr.

Abstract

The nuclear factor (NF)-κB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-κB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor α (TNFα) receptor 1 signaling complex (TNF-RSC) and attenuates TNFα-induced NF-κB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFα-induced increase in IκB kinase (IKK) activity, as well as the expression of NF-κB target genes. TNFα induced the recruitment of MST1 to TNF-RSC and its interaction with HOIP, the catalytic component of the E3 ligase linear ubiquitin assembly complex (LUBAC). Furthermore, MST1 activated in response to TNFα stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKKγ. Together, our findings suggest that MST1 negatively regulates TNFα-induced NF-κB signaling by targeting LUBAC.

KEYWORDS:

HOIP; LUBAC; MST1; NF-κB; TNFα; TNFα receptor 1 signaling complex; TRAF2; inflammation; macrophage; ubiquitination

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