Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation

Dysregulated interleukin-17 (IL-17) expression and its downstream signaling is strongly linked to inflammatory bowel diseases (IBDs). However, the molecular mechanisms by which the function of ROR gamma t, the transcription factor of IL-17 is regulated remains elusive. By a mass spectrometry-based approach, we identify that Pak2, a serine (S)/threonine (T) kinase, directly associates with ROR gamma t. Pak2 recognizes a conserved KRLS motif within ROR gamma t and phosphorylates the S-316 within this motif. Genetic deletion of Pak2 in Th17 cells reduces ROR gamma t phosphorylation, increases IL-17 expression, and induces severe colitis upon adoptive transfer to Rag1(-/-) mice. Similarly, reconstitution of ROR gamma t-S316A mutant in Rorc(-/-) Th17 cells enhances IL-17 expression and colitis severity. Mechanistically, we demonstrate that Pak2-mediated phosphorylation causes a conformational change resulting in exposure of the ubiquitin ligase Itch interacting PPLY motif and degradation of ROR gamma t. Thus, we have uncovered a mechanism by which the activity of ROR gamma t is regulated that can be exploited therapeutically.

Automated summary

Dysregulated interleukin-17 expression and its downstream signaling is strongly linked to inflammatory bowel diseases. We identified that Pak2 directly interacts with ROR gamma t and regulates its activity through phosphorylation.