1. Academic Validation
  2. One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages

One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages

  • Mol Cell. 2019 Sep 19;75(6):1147-1160.e5. doi: 10.1016/j.molcel.2019.06.039.
Weiwei Yu 1 Zhen Wang 2 Kailian Zhang 2 Zhexu Chi 2 Ting Xu 2 Danlu Jiang 2 Sheng Chen 2 Wenxin Li 1 Xuyan Yang 3 Xue Zhang 4 Yingliang Wu 5 Di Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 2 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3 Department of Rheumatology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: ylwu@whu.edu.cn.
  • 6 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Orthopedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: diwang@zju.edu.cn.
Abstract

Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but little is known about the biochemical underpinnings of this process. Here, we find that lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1β (IL-1β) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-1β production. We therefore identify a synergistic effect of glucose and amino acid metabolism on orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.

Keywords

H3K36me3; S-adenosylmethionine; amino-acid metabolism; epigenetic reprogramming; glycolysis offshoots; inflammation; one-carbon metabolism.

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