As one of the core components of the switching or sucrose non-fermentable (SWI/SNF) complex, SMARCC1 (BAF155, SRG3) plays essential roles in activation of late inflammatory genes in response to microbial challenge. However, little is known about the mechanism of how SMARCC1 regulates the inflammatory innate response. Via functional screening, we identify the nuclear E3 ubiquitin ligase RNF138 as a negative regulator in the inflammatory innate response and show that RNF138 interacts with SMARCC1 and mediates its K48-linked polyubiquitination at position Lys643 and proteasomal degradation. As a result, the catalytic activity of RNF138 fine-tunes the kinetics of late inflammatory gene transcription by inhibiting chromatin remodeling at SWI/SNF-regulated gene loci. Reduced RNF138 and increased SMARCC1 in monocytes of rheumatoid arthritis patients are observed. These results provide mechanistic insight into the interplay among nucleosome remodeling, inflammation, and ubiquitylation and underscore the important role of the E3 ubiquitin ligases in controlling the extent and duration of inflammatory responses.

作为开关或蔗糖不可发酵 (SWI/SNF) 复合物的核心成分之一，SMARCC1（BAF155、SRG3）在响应微生物挑战的晚期炎症基因激活中发挥着重要作用。然而，人们对 SMARCC1 调节炎症先天反应的机制知之甚少。通过功能筛选，我们确定核 E3 泛素连接酶 RNF138 是炎症先天反应中的负调节因子，并表明 RNF138 与 SMARCC1 相互作用，并介导其在 Lys643 位点的 K48 连接多泛素化和蛋白酶体降解。因此，RNF138 的催化活性通过抑制 SWI/SNF 调节基因位点的染色质重塑来微调晚期炎症基因转录的动力学。类风湿关节炎患者的单核细胞中 RNF138 减少，SMARCC1 增加。这些结果提供了对核小体重塑、炎症和泛素化之间相互作用的机制见解，并强调了 E3 泛素连接酶在控制炎症反应的程度和持续时间中的重要作用。