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一个LKB1-线粒体轴控制TH17效应子功能
2022-09-30 23:32

德国马克斯普朗克免疫生物学和表观遗传学研究所Erika L. Pearce小组发现,一个LKB1-线粒体轴控制TH17效应子功能。这一研究成果于2022年9月28日在线发表在国际学术期刊《自然》上。

研究人员发现,与其他CD4+T细胞亚群不同,T辅助17(TH17)细胞具有融合的线粒体和紧密的嵴。T细胞特异性删除调节线粒体内膜融合和嵴形态的视神经萎缩1(OPA1)表明,TH17细胞需要OPA1来控制三羧酸(TCA)循环,而不是呼吸。OPA1的缺失放大了谷氨酰胺的氧化,导致NADH/NAD+平衡受损,TCA循环代谢物和2-羟基戊二酸的积累,这是一种影响表观遗传的代谢物。多组学方法显示,丝氨酸/苏氨酸激酶肝脏相关激酶B1(LKB1)通过调节TCA循环代谢和转录重塑,将线粒体功能与TH17细胞中的细胞因子表达联系起来。线粒体膜的破坏激活了LKB1,它抑制了IL-17的表达。LKB1的缺失恢复了线粒体膜破坏的TH17细胞的IL-17表达,纠正了异常的TCA循环谷氨酰胺通量,平衡了NADH/NAD+,从而防止了丝氨酸生物合成酶磷酸甘油酸脱氢酶(PHGDH)的杂乱活动产生2-羟基戊二酸。

这些发现确定OPA1是决定TH17细胞功能的一个主要因素,并发现LKB1是连接线粒体线索和TH17细胞效应程序的传感器。

据介绍,CD4+T细胞分化需要新陈代谢的重新规划,从而满足增殖和效应功能的生物能量需求,并执行特定的转录程序。线粒体膜动态维持线粒体过程,包括呼吸和TCA循环代谢,但线粒体膜重塑是否协调了CD4+T细胞分化仍不清楚。

附:英文原文

Title: An LKB1–mitochondria axis controls TH17 effector function

Author: Baixauli, Francesc, Piletic, Klara, Puleston, Daniel J., Villa, Matteo, Field, Cameron S., Flachsmann, Lea J., Quintana, Andrea, Rana, Nisha, Edwards-Hicks, Joy, Matsushita, Mai, Stanczak, Michal A., Grzes, Katarzyna M., Kabat, Agnieszka M., Fabri, Mario, Caputa, George, Kelly, Beth, Corrado, Mauro, Musa, Yaarub, Duda, Katarzyna J., Mittler, Gerhard, OSullivan, David, Sesaki, Hiromi, Jenuwein, Thomas, Buescher, Joerg M., Pearce, Edward J., Sanin, David E., Pearce, Erika L.

Issue&Volume: 2022-09-28

Abstract: CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1,2,3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate—a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.

DOI: 10.1038/s41586-022-05264-1

Source: https://www.nature.com/articles/s41586-022-05264-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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