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.