| First Author | Kathania M | Year | 2022 |
| Journal | Cell Rep | Volume | 40 |
| Issue | 11 | Pages | 111345 |
| PubMed ID | 36103814 | Mgi Jnum | J:345456 |
| Mgi Id | MGI:7345384 | Doi | 10.1016/j.celrep.2022.111345 |
| Citation | Kathania M, et al. (2022) Pak2-mediated phosphorylation promotes RORgammat ubiquitination and inhibits colonic inflammation. Cell Rep 40(11):111345 |
| abstractText | 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 RORgammat, 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 RORgammat. Pak2 recognizes a conserved KRLS motif within RORgammat and phosphorylates the S-316 within this motif. Genetic deletion of Pak2 in Th17 cells reduces RORgammat phosphorylation, increases IL-17 expression, and induces severe colitis upon adoptive transfer to Rag1(-/-) mice. Similarly, reconstitution of RORgammat-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 RORgammat. Thus, we have uncovered a mechanism by which the activity of RORgammat is regulated that can be exploited therapeutically. |
