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
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一碳代谢支持 S-腺苷甲硫氨酸和组蛋白甲基化以驱动炎症巨噬细胞
DOI：
10.1016/j.molcel.2019.06.039
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发表时间：
2019
期刊：
影响因子：
16
通讯作者：
Wang Di
中科院分区：
文献类型：
--
作者：
Yu Weiwei;Wang Zhen;Zhang Kailian;Chi Zhexu;Xu Ting;Jiang Danlu;Chen Sheng;Li Wenxin;Yang Xuyan;Zhang Xue;Wu Yingliang;Wang Di
活化的巨噬细胞调整其代谢途径以驱动促炎表型，但对该过程的生化基础知之甚少。在这里，我们发现脂多糖（LPS）激活戊糖磷酸途径，丝氨酸合成途径和一碳代谢，其协同作用驱动白细胞介素-1 β（IL-1β）表达的表观遗传重编程。葡萄糖衍生的核糖和由葡萄糖和丝氨酸代谢提供的一碳单元通过novoATP合成协同整合到甲硫氨酸循环中，并在LPS诱导的炎症期间促进S-腺苷甲硫氨酸（SAM）的产生。这些供给SAM生成的代谢途径的损害导致抗炎结果，暗示SAM是炎性巨噬细胞的必需代谢物。在机制上，SAM生成维持相对高的SAM：S-腺苷高半胱氨酸比率以支持组蛋白H3赖氨酸36三甲基化以产生IL-1β。因此，我们确定了葡萄糖和氨基酸代谢对协调SAM可用性的协同作用，SAM可用性与炎症的染色质状态密切相关。
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 throughde novoATP 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.