Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; and University of Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; and University of Chinese Academy of Sciences, Beijing, China
J Immunol. 2021 Dec 15;207(12):3090-3097. doi: 10.4049/jimmunol.2100561. Epub 2021 Nov 19.
The proinflammatory cytokine IL-1β is a crucial mediator of inflammatory responses. IL-1β-induced signaling is finely regulated by various mechanisms, and its imbalance is involved in a variety of diseases. In this study, we identified FAM177A1, a protein of unknown function, as a negative regulator of IL-1β-induced signaling in human cells. Overexpression of FAM177A1 inhibited IL-1β-triggered activation of NF-κB and transcription of inflammatory genes, whereas knockdown of FAM177A1 showed the opposite effects. Mechanistically, FAM177A1 competitively bound to the E3 ubiquitin ligase TRAF6 and impaired its interaction with the E2-conjugating enzyme Ubc13; therefore, it inhibited TRAF6-mediated polyubiquitination and recruitment of downstream signaling molecules. These findings reveal a function of FAM177A1 and promote our understanding of the regulatory mechanisms of IL-1β-induced inflammatory responses.
促炎细胞因子 IL-1β 是炎症反应的关键介质。IL-1β 诱导的信号转导受到多种机制的精细调节，其失衡与多种疾病有关。在本研究中，我们鉴定了 FAM177A1，一种功能未知的蛋白质，作为人细胞中 IL-1β 诱导信号的负调节剂。FAM177A1 的过表达抑制了 IL-1β 触发的 NF-κB 激活和炎症基因的转录，而 FAM177A1 的敲低则显示出相反的效果。在机制上，FAM177A1 竞争性地与 E3 泛素连接酶 TRAF6 结合，并损害其与 E2 连接酶 Ubc13 的相互作用；因此，它抑制了 TRAF6 介导的多泛素化和下游信号分子的募集。这些发现揭示了 FAM177A1 的功能，并促进了我们对 IL-1β 诱导的炎症反应的调节机制的理解。
