Yuan Gongsheng, Yang Shuting, Yang Shuying
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Genes Dis. 2021 Aug 26;9(5):1357-1367. doi: 10.1016/j.gendis.2021.08.005. eCollection 2022 Sep.
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 , , and 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。在此，我们鉴定出巨噬细胞中G蛋白信号调节因子12（RGS12），其在炎症过程中促进泛素与IκB之间的结合。我们还发现RGS12通过增强泛素化促进IκB的降解，而该过程可被MG132抑制。此外，增加的泛素化进一步抑制MTAP的表达，MTAP可间接激活IκB的磷酸化。最后，由于IκB的降解，NF-κB易位至细胞核并在炎症过程中进一步促进细胞因子如 、 和 的基因表达。重要的是，RGS12缺陷可预防手术或化学诱导的OA中的泛素化和炎症。我们得出结论，巨噬细胞中RGS12的缺失会干扰IκB的泛素化和降解，从而预防炎症和软骨损伤。我们的结果为RGS12在促进炎症和调节免疫信号中的相关性提供了证据。
