Sumoylation of RORγt regulates T<sub>H</sub>17 differentiation and thymocyte development.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30451821.
- Also identified by DOI 10.1038/s41467-018-07203-z and PMC identifier 6242824.
- 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
RORγt controls the differentiation of T<sub>H</sub>17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). RORγt also regulates thymocyte development and lymph node genesis. Here we show that the function of RORγt is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens T<sub>H</sub>17 differentiation and delays the progression of thymic CD8<sup>+</sup> immature single-positive cells (ISPs). RORγt is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORγt sumoylation, leading to impaired T<sub>H</sub>17 differentiation, resistance to T<sub>H</sub>17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer's patches. Mechanistically, sumoylation of RORγt-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance RORγt transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating RORγt function, and reveals new drug targets for preventing T<sub>H</sub>17-mediated autoimmunity.
Medical subject headings
- Encephalomyelitis, Autoimmune, Experimental
- Nuclear Receptor Subfamily 1, Group F, Member 3
- Protein Processing, Post-Translational
- Th17 Cells
- Thymocytes
- Thymus Gland
- Ubiquitins