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
Department of Life Sciences, Korea University, Seoul 02841, South Korea.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
Mol Cell. 2019 Mar 21;73(6):1138-1149.e6. doi: 10.1016/j.molcel.2019.01.022. Epub 2019 Feb 21.
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.
核因子（NF）-κB信号通路在炎症和免疫反应中起核心作用，NF-κB信号的异常激活与多种人类疾病有关。在此，我们表明哺乳动物类Ste20激酶1（MST1）是肿瘤坏死因子α（TNFα）受体1信号复合物（TNF-RSC）中一个先前未被认识的成分，并减弱TNFα诱导的NF-κB信号传导。在小鼠胚胎成纤维细胞和骨髓来源的巨噬细胞中对MST1进行基因敲除增强了TNFα诱导的IκB激酶（IKK）活性增加以及NF-κB靶基因的表达。TNFα诱导MST1募集到TNF-RSC并使其与HOIP相互作用，HOIP是E3连接酶线性泛素组装复合物（LUBAC）的催化成分。此外，响应TNFα刺激而激活的MST1介导HOIP的磷酸化，从而抑制NEMO/IKKγ的LUBAC依赖性线性泛素化。总之，我们的研究结果表明MST1通过靶向LUBAC负向调节TNFα诱导的NF-κB信号传导。
