Ubiquitination has important functions in osteoarthritis (OA), yet the mechanism remains unclear. Here, we identify the regulator of G protein signaling 12 (RGS12) in macrophages, which promotes the association between ubiquitin and IκB during inflammation. We also find that RGS12 promotes the degradation of IκB through enhancing the ubiquitination whereas the process can be inhibited by MG132. Moreover, the increased ubiquitination further inhibits the expression of MTAP, which can indirectly activate the phosphorylation of IκB. Finally, due to the degradation of IκB, the NF-κB translocates into the nucleus and further promotes the gene expression of cytokines such as IL1β, IL6, and TNFα during inflammation. Importantly, RGS12 deficiency prevents ubiquitination and inflammation in surgically or chemically induced OA. We conclude that the lack of RGS12 in macrophages interferes with the ubiquitination and degradation of IκB, thereby preventing inflammation and cartilage damage. Our results provide evidence for the relevance of RGS12 in promoting inflammation and regulating immune signaling.

泛素化在骨关节炎 (OA) 中具有重要作用，但其机制仍不清楚。在这里，我们确定了巨噬细胞中 G 蛋白信号转导 12 (RGS12) 的调节因子，它促进炎症期间泛素和 IκB 之间的关联。我们还发现 RGS12 通过增强泛素化促进 IκB 的降解，而该过程可以被 MG132 抑制。此外，泛素化的增加进一步抑制了 MTAP 的表达，从而间接激活了 IκB 的磷酸化。最后，由于 IκB 的降解，NF-κB 易位进入细胞核，进一步促进细胞因子如IL1β、IL6和TNFα的基因表达炎症期间。重要的是，RGS12 缺乏可防止手术或化学诱导的 OA 中的泛素化和炎症。我们得出结论，巨噬细胞中 RGS12 的缺乏会干扰 IκB 的泛素化和降解，从而防止炎症和软骨损伤。我们的结果为 RGS12 在促进炎症和调节免疫信号传导方面的相关性提供了证据。