MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity
MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity
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DOI：
10.1016/j.molcel.2019.01.022
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发表时间：
2019-03-21
期刊：
影响因子：
16
通讯作者：
Choi, Eui-Ju
中科院分区：
文献类型：
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作者：
Lee, In Young;Lim, Jane Melissa;Choi, Eui-Ju
核因子（NF）-κ B途径在炎症和免疫应答中起核心作用，其中NF-κ B信号传导的异常激活涉及各种人类病症。在这里，我们表明，哺乳动物ste 20样激酶1（MST 1）是一个以前未认识的组成部分，肿瘤坏死因子α（TNF α）受体1信号传导复合物（TNF-RSC），并减弱TNF α诱导的NF-κ B信号。小鼠胚胎成纤维细胞和骨髓源性巨噬细胞中MST 1的基因切除增强了TNF α诱导的I κ B激酶（IKK）活性增加以及NF-κ B靶基因表达。TNF α诱导MST 1向TNF-RSC的募集及其与HOIP的相互作用，HOIP是E3连接酶线性泛素组装复合物（LUBAC）的催化组分。此外，响应于TNF α刺激而激活的MST 1介导HOIP的磷酸化，从而抑制NEMO/IKK γ的LUBAC依赖性线性泛素化。总之，我们的研究结果表明MST 1通过靶向LUBAC负调节TNF α诱导的NF-κ B信号传导。
The nuclear factor (NF)-kappa B pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-kappa B 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 alpha (TNF alpha) receptor 1 signaling complex (TNF-RSC) and attenuates TNF alpha-induced NF-kappa B signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNF alpha-induced increase in I kappa B kinase (IKK) activity, as well as the expression of NF-kappa B target genes. TNF alpha 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 TNF alpha stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKK gamma. Together, our findings suggest that MST1 negatively regulates TNF alpha-induced NF-kappa B signaling by targeting LUBAC.