Abstract
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 RORγt, 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 RORγt. Pak2 recognizes a conserved KRLS motif within RORγt and phosphorylates the S-316 within this motif. Genetic deletion of Pak2 in Th17 cells reduces RORγt phosphorylation, increases IL-17 expression, and induces severe colitis upon adoptive transfer to Rag1−/− mice. Similarly, reconstitution of RORγt-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 RORγt. Thus, we have uncovered a mechanism by which the activity of RORγt is regulated that can be exploited therapeutically.
Original language | English |
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Article number | 111345 |
Pages (from-to) | 111345 |
Journal | Cell Reports |
Volume | 40 |
Issue number | 11 |
DOIs | |
State | Published - Sep 13 2022 |
Keywords
- CP: Immunology
- Pak2
- RORγt
- interleukin-17
- posttranslational modification
- ulcerative colitis