{"title":"赖氨酸乙酰转移酶 6A 通过对自身免疫中的葡萄糖代谢进行表观遗传学重编程来维持 CD4+ T 细胞反应。","authors":"Jia-Yao Fu, Shi-Jia Huang, Bao-Li Wang, Jun-Hao Yin, Chang-Yu Chen, Jia-Bao Xu, Yan-Lin Chen, Shuo Xu, Ting Dong, Hao-Nan Zhou, Xin-Yi Ma, Yi-Ping Pu, Hui Li, Xiu-Juan Yang, Li-Song Xie, Zhi-Jun Wang, Qi Luo, Yan-Xiong Shao, Lei Ye, Zi-Rui Zong, Xin-Di Wei, Wan-Wen Xiao, Shu-Tong Niu, Yi-Ming Liu, He-Ping Xu, Chuang-Qi Yu, Sheng-Zhong Duan, Ling-Yan Zheng","doi":"10.1016/j.cmet.2023.12.016","DOIUrl":null,"url":null,"abstract":"<p><p>Augmented CD4<sup>+</sup> T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4<sup>+</sup> T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4<sup>+</sup> T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4<sup>+</sup> T cell subsets in vitro, and mice with KAT6A-deficient CD4<sup>+</sup> T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4<sup>+</sup> T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lysine acetyltransferase 6A maintains CD4<sup>+</sup> T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.\",\"authors\":\"Jia-Yao Fu, Shi-Jia Huang, Bao-Li Wang, Jun-Hao Yin, Chang-Yu Chen, Jia-Bao Xu, Yan-Lin Chen, Shuo Xu, Ting Dong, Hao-Nan Zhou, Xin-Yi Ma, Yi-Ping Pu, Hui Li, Xiu-Juan Yang, Li-Song Xie, Zhi-Jun Wang, Qi Luo, Yan-Xiong Shao, Lei Ye, Zi-Rui Zong, Xin-Di Wei, Wan-Wen Xiao, Shu-Tong Niu, Yi-Ming Liu, He-Ping Xu, Chuang-Qi Yu, Sheng-Zhong Duan, Ling-Yan Zheng\",\"doi\":\"10.1016/j.cmet.2023.12.016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Augmented CD4<sup>+</sup> T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4<sup>+</sup> T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4<sup>+</sup> T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4<sup>+</sup> T cell subsets in vitro, and mice with KAT6A-deficient CD4<sup>+</sup> T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4<sup>+</sup> T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.</p>\",\"PeriodicalId\":93927,\"journal\":{\"name\":\"Cell metabolism\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-03-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell metabolism\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cmet.2023.12.016\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cmet.2023.12.016","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/17 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
自身免疫中 CD4+ T 细胞反应增强的特点是广泛的代谢重编程。然而,驱动 CD4+ T 细胞代谢适应的表观遗传分子在很大程度上仍然未知。在这里,我们发现赖氨酸乙酰转移酶 6A (KAT6A)--一种临床上与自身免疫相关的表观遗传调控因子--协调了 CD4+ T 细胞中葡萄糖的代谢重编程。体外促炎性 CD4+ T 细胞亚群的增殖和分化需要 KAT6A,CD4+ T 细胞缺乏 KAT6A 的小鼠对实验性自身免疫性脑脊髓炎和结肠炎的易感性较低。从机理上讲,KAT6A 可协调多个糖酵解基因所在染色质的组蛋白乙酰化丰度,从而影响葡萄糖代谢重编程和随后的 CD4+ T 细胞反应。在小鼠模型中使用 KAT6A 小分子抑制剂治疗显示,针对自身免疫中的 KAT6A 有很高的治疗价值。我们的研究为免疫代谢的表观遗传编程提供了新的见解,并为自身免疫患者提出了潜在的治疗目标。
Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.
Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.