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Sumoylation of ROR?t regulates TH17 differentiation and thymocyte development.

ABSTRACT: ROR?t controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). ROR?t also regulates thymocyte development and lymph node genesis. Here we show that the function of ROR?t is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens TH17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs). ROR?t is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents ROR?t sumoylation, leading to impaired TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer's patches. Mechanistically, sumoylation of ROR?t-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance ROR?t transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating ROR?t function, and reveals new drug targets for preventing TH17-mediated autoimmunity.

SUBMITTER: He Z

PROVIDER: S-EPMC6242824 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Sumoylation of RORγt regulates TH17 differentiation and thymocyte development.

He Zhiheng Z Zhang Jing J Huang Zhaofeng Z Du Qian Q Li Ning N Zhang Qiang Q Chen Yuan Y Sun Zuoming Z

Nature communications 20181119 1

RORγt controls the differentiation of TH17 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 TH17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs). RORγt is SUMO3-modified by E3 ligas ...[more]

PMID: 30451821

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Project description:BACKGROUND:Toll-like receptor 4 (TLR4) is well known for activating the innate immune system; however, it is also highly expressed in adaptive immune cells, such as CD4+ T-helper 17 (Th17) cells, which play a key role in multiple sclerosis (MS) pathology. However, the function and governing mechanism of TLR4 in Th17 remain unclear. METHODS:The changes of TLR4 in CD4+ T cells from MS patients and experimental autoimmune encephalomyelitis (EAE) mice were tested. TLR4-deficient (TLR4-/-) naïve T cells were induced in vitro and transferred into Rag1-/- mice to measure Th17 differentiation and EAE pathology. DNA sequence analyses combining with deletion fragments and mutation analyses, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to explore the mechanism of TLR4 signaling pathway in regulating Th17 differentiation. RESULTS:The levels of TLR4 were increased in CD4+ Th17 cells both from MS patients and EAE mice, as well as during Th17 differentiation in vitro. TLR4-/- CD4+ naïve T cells inhibited their differentiation into Th17, and transfer of TLR4-/- CD4+ naïve T cells into Rag1-/- mice was defective in promoting EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. TLR4 signal enhanced Th17 differentiation by activating RelA, downregulating the expression of miR-30a, a negative regulator of Th17 differentiation. Inhibition of RelA activity increased miR-30a level, but decreased Th17 differentiation rate. Furthermore, RelA directly regulated the expression of miR-30a via specific binding to a conserved element of miR-30a gene. CONCLUSIONS:TLR4-/- CD4+ naïve T cells are inadequate in differentiating to Th17 cells both in vitro and in vivo. TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation via direct binding of RelA to the regulatory element of miR-30a gene. Our results indicate modulating TLR4-RelA-miR-30a signal in Th17 may be a therapeutic target for Th17-mediated neurodegeneration in neuroinflammatory diseases.

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Sumoylation of ROR?t regulates TH17 differentiation and thymocyte development.

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Sumoylation of RORγt regulates T<sub>H</sub>17 differentiation and thymocyte development.

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