Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation

Cell Rep. 2022 Sep 13;40(11):111345. doi: 10.1016/j.celrep.2022.111345.

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.

Keywords: CP: Immunology; Pak2; RORγt; interleukin-17; posttranslational modification; ulcerative colitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis*
  • Inflammation
  • Interleukin-17 / metabolism
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3* / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3* / metabolism
  • Phosphorylation
  • Ubiquitination
  • p21-Activated Kinases / metabolism*

Substances

  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Pak2 protein, mouse
  • p21-Activated Kinases