Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation

Mahesh Kathania, Ritesh Kumar, Elviche Taskem Lenou, Venkatesha Basrur, Arianne L. Theiss, Jonathan Chernoff, K. Venuprasad

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Article number111345
JournalCell Reports
Volume40
Issue number11
DOIs
StatePublished - Sep 13 2022

Keywords

  • CP: Immunology
  • interleukin-17
  • Pak2
  • posttranslational modification
  • RORγt
  • ulcerative colitis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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