Abstract Background Although biological agents make breakthrough in treatment for inflammatory bowel disease (IBD), it cannot induce and sustain long-term remission and mucosal healing. RING finger 187 (RNF187), also named as RING domain AP-1 co-activator-1, is one of the RING family. RNF187 is a RING domain-containing ubiquitin E3 ligase and its protein expression is unstable due to K48-linked autoubiquitination. Previous reported that RNF187 functions as a c-Jun coactivator to promote AP-1 transactivation, which is regulated by methyltransferase PRMT1 mediated arginine methylation or the phosphorylation–ubiquitination crosstalk in TRIM7 and MSK1. However, the biological function of RNF187 in IBD remains unclear. Methods The functions and mechanism of RNF187 in IBD were detected in vitro and in Villin-Rnf187flox/flox mice. Cell permeable recombined fusion protein TAT-RNF187 was injected intraperitoneally into dextran sulfate sodium (DSS)-induced colitis in mice to assess its anti-inflammatory effects. Results We found that RNF187 could be as an anti-inflammatory protein to inhibit the development of intestinal inflammation in vitro and in Villin-Rnf187flox/flox mice. Mechanistically, we identify an ubiquitin E3 ligase -independent function of RNF187 that C-term 163-265 domain is required for RNF187 to interact with the LZ domain of IKKα/β, thus antagonizing the IKK complex formation and subsequent activation to inhibit intestinal inflammation. In response to TNF-α, IKKα-mediated phosphorylation of RNF187 promoted its autoubiquitylation at K195&K223 and subsequent degradation of RNF187. More importantly, we generated a TAT-RNF187 recombined protein and demonstrated that TAT-RNF187 recombined protein significanlty alleviates intestinal inflammation and improves therapeutic efficacy of infliximab. Consistent with the above results, RNF187 expression was decreased in intestinal inflammation in colon tissues from IBD patients and were associated with the therapeutic effect of infliximab. Conclusion In summary, this study provides evidence that RNF187 is an important negative regulator of intestinal inflammation and reveals that RNF187 as an IKK-interactor to antagonize the IKK complex formation to inhibit intestinal inflammation, and clarifies that IKKα phosphorylates RNF187 to promote its autoubiquitylation. These results reveal a new negative feedback loop between RNF187 and IKKα, which provides a new therapeutic strategy of supplying with RNF187 fusion protein for patients with refractory IBD. Conflict of interest: Dr. Xu, Weimin: No conflict of interest Hua, Zhebin: No conflict of interest Dai, Zhujiang: No conflict of interest Liu, Chen-Ying: No conflict of interest Du, Peng: No conflict of interest
Xu et al. (Thu,) studied this question.