SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2.

Autor:	Singh AK; Baylor Institute for Immunology Research, Baylor Scott & White Research Institute, Dallas, TX, 75204, USA., Khare P; Baylor Institute for Immunology Research, Baylor Scott & White Research Institute, Dallas, TX, 75204, USA., Obaid A; Baylor Institute for Immunology Research, Baylor Scott & White Research Institute, Dallas, TX, 75204, USA., Conlon KP; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Basrur V; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., DePinho RA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Venuprasad K; Baylor Institute for Immunology Research, Baylor Scott & White Research Institute, Dallas, TX, 75204, USA. venuprasad.poojary@BSWHealth.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Oct 30; Vol. 9 (1), pp. 4515. Date of Electronic Publication: 2018 Oct 30.
DOI:	10.1038/s41467-018-06924-5
Abstrakt:	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 -/- 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 + 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.
Databáze:	MEDLINE
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