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

• Published in: Molecular cell Vol. 73; no. 6; pp. 1138 - 1149.e6
• Main Authors: Lee, In Young, Lim, Jane Melissa, Cho, Hyunchu, Kim, Eunju, Kim, Yeonsil, Oh, Hye-Kyung, Yang, Woo Seok, Roh, Kyung-Hye, Park, Hyun Woo, Mo, Jung-Soon, Yoon, Je-Hyun, Song, Hyun Kyu, Choi, Eui-Ju
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2019
• Subjects: HOIP; inflammation; LUBAC; macrophage; MST1; NF-κB; TNFα; TNFα receptor 1 signaling complex; TRAF2; ubiquitination; NF-κB; TNFα; ubiquitination; inflammation; MST1; TNFα receptor 1 signaling complex; macrophage; TRAF2; LUBAC; HOIP
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.01.022

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. [Display omitted] •TNFα induces the recruitment of MST1 to the TNFR1 signaling complex (TNF-RSC)•TRAF2 is required for the TNFα-induced activation of MST1 within the TNF-RSC•MST1 phosphorylates HOIP in TNF-RSC, thereby inhibiting an E3 ligase activity of LUBAC•MST1 attenuates the LUBAC-mediated activation of the NF-κB pathway Lee et al. identify MST1 as a component of TNF-RSC that phosphorylates HOIP at serine 1,066 and thereby inhibits the linear ubiquitin chain-forming activity of LUBAC in a TRAF2-dependent manner. MST1, by inhibiting an E3 ligase activity of HOIP, negatively regulates the NF-κB-dependent inflammatory gene expression induced by TNFα.