美国斯坦福大学医学院Cornelia M. Weyand研究团队发现促炎性和组织侵袭性T细胞中的琥珀酰辅酶A连接酶缺乏。相关论文于2020年12月1日发表在《细胞—代谢》杂志上。

研究人员表示，类风湿关节炎（RA）中的自身免疫性T细胞在线粒体耗氧量和ATP产生方面存在缺陷。

研究人员发现，抑制琥珀酸-CoA连接酶（SUCLG2）的GDP形成β亚基是潜在的异常。缺乏SUCLG2的T细胞将三羧酸（TCA）循环从氧化方向改变为还原方向，积累了α-酮戊二酸、柠檬酸和乙酰辅酶A（AcCoA），并分化为促炎性效应细胞。在AcCoA^hi RA T细胞中，微管蛋白乙酰化作用可稳定微管细胞骨架并将线粒体定位在核周位置，从而导致细胞极化、尾足形成、T细胞迁移和组织浸润。

在组织中，缺乏SUCLG2的T细胞可作为产生细胞因子的效应细胞发挥功能，并且是过度炎症的，可以通过补充酶来纠正这一缺陷。通过微管蛋白乙酰转移酶敲低防止T细胞微管蛋白乙酰化足以抑制滑膜炎。这些数据将线粒体衰竭和AcCoA供过于求与自身免疫性组织炎症联系起来。

附：英文原文

Title: Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells

Author: Bowen Wu, Jingtao Qiu, Tuantuan V. Zhao, Yanan Wang, Toshihisa Maeda, Isabel N. Goronzy, Mitsuhiro Akiyama, Shozo Ohtsuki, Ke Jin, Lu Tian, Jrg J. Goronzy, Cornelia M. Weyand

Issue&Volume: 2020/12/01

Abstract: Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygenconsumption and ATP production. Here, we identified suppression of the GDP-formingβ subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficientT cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductivedirection, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiatedinto pro-inflammatory effector cells. In AcCoAhi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positionedmitochondria in a perinuclear location, resulting in cellular polarization, uropodformation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficientT cells functioned as cytokine-producing effector cells and were hyperinflammatory,a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylationby tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. Thesedata link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

DOI: 10.1016/j.cmet.2020.10.025

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30594-5