SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30375383.
- Also identified by DOI 10.1038/s41467-018-06924-5 and PMC identifier 6207785.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined. Here we show that SUMO-conjugating enzyme Ubc9 interacts with a conserved GKAE motif in ROR-γt to induce SUMOylation of ROR-γt and suppress IL-17 expression. Th17 cells expressing SUMOylation-defective ROR-γt are highly colitogenic upon transfer to Rag1<sup>-/-</sup> mice. Mechanistically, SUMOylation of ROR-γt facilitates the binding of HDAC2 to the IL-17 promoter and represses IL-17 transcription. Mice with conditional deletion of HDAC2 in CD4<sup>+</sup> T cells have elevated IL-17 expression and severe colitis. The identification of the Ubc9/ROR-γt/HDAC2 axis that governs IL-17 expression may open new venues for the development of therapeutic measures for inflammatory disorders.
Medical subject headings
- Histone Deacetylase 2
- Interleukin-17
- Nuclear Receptor Subfamily 1, Group F, Member 3
- Sumoylation
- Th17 Cells
- Ubiquitin-Conjugating Enzymes