Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling

• 成果类型: Article
• 署名作者: Chen, Yali; Chen, Kun; Zhu, Ha; Qin, Hua; Liu, Juan; Cao, Xuetao
• 署名单位: Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Naval Medical University; Tongji University; Nankai University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9570
• DOI: 10.1073/pnas.2314561121
• 发表日期: 2024-02-20
• 关键词: er stress; metabolism; COORDINATION; methylation; epigenetics

摘要

Coordinated metabolic reprogramming and epigenetic remodeling are critical for mod-ulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 develop-ment but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up- regulates transcriptional expression of lysophosphatidylcholine acyltrans-ferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4- mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF- 1 alpha tran-scriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.