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

Authors :
Yali Chen
Kun Chen
Ha Zhu
Hua Qin
Juan Liu
Xuetao Cao
Source :
Proceedings of the National Academy of Sciences of the United States of America. 2/20/2024, Vol. 121 Issue 8, p1-20. 31p.
Publication Year :
2024

Abstract

Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating 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 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 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-1a transcriptional 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
121
Issue :
8
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
176171482
Full Text :
https://doi.org/10.1073/pnas.2314561121