Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation

Abstract Dysregulated Interleukin (IL)-17 expression and its downstream signaling is strongly linked to inflammatory bowel diseases (IBD). However, the molecular mechanisms by which function of RORγt, transcription factor IL-17, regulated remains elusive, absolutely necessary develop advanced strategies inhibit IL-17-mediated inflammation. By mass spectrometry-based approach, we have identified that Pak2, a Ser/Thr kinase, directly associates with RORγt. Pak2 recognizes conserved KRLS motif within RORγt phosphorylated Serine (S) 316 this motif. Genetic deletion in Th17 cells resulted reduced phosphorylation, increased IL-17 severe colitis upon adoptive transfer Rag1 −/−mice. Similarly, reconstitution RORγt-S316A mutant Rorc −/−Th17 enhanced severity. Mechanistically, demonstrate Pak2-mediated phosphorylation causes conformational change resulting exposure ubiquitin ligase Itch interacting PPLY degradation Thus, uncovered novel mechanism activity can be exploited therapeutically. This work was supported funds from National Institutes Health (R01-DK115668 R01-AI155786) Cancer Prevention Research Institute Texas (RP160577 RP190527), translational pilot project grant Harold C. Simmons Comprehensive Center, UT Southwestern Medical Center (23001045) K.V., R01-DK117001 K.V. A.L.T.