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Sumoylation of RORγt regulates TH17 differentiation and thymocyte development

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Listed:
  • Zhiheng He

    (Beckman Research Institute of City of Hope)

  • Jing Zhang

    (Beckman Research Institute of City of Hope
    Irell & Manella Graduate School of Biological Sciences, City of Hope)

  • Zhaofeng Huang

    (Sun Yat-sen University)

  • Qian Du

    (Beckman Research Institute of City of Hope)

  • Ning Li

    (Fudan Univerity)

  • Qiang Zhang

    (Tianjin Geriatrics Institute)

  • Yuan Chen

    (Beckman Research Institute of City of Hope)

  • Zuoming Sun

    (Beckman Research Institute of City of Hope)

Abstract

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 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORγt 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 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 TH17-mediated autoimmunity.

Suggested Citation

  • Zhiheng He & Jing Zhang & Zhaofeng Huang & Qian Du & Ning Li & Qiang Zhang & Yuan Chen & Zuoming Sun, 2018. "Sumoylation of RORγt regulates TH17 differentiation and thymocyte development," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07203-z
    DOI: 10.1038/s41467-018-07203-z
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