促炎和組織侵襲性T細胞存在琥珀醯輔酶a連接酶缺乏
作者：
小柯機器人發布時間：2020/12/2 21:38:57
美國史丹福大學醫學院Cornelia M. Weyand研究團隊發現促炎性和組織侵襲性T細胞中的琥珀醯輔酶A連接酶缺乏。相關論文於2020年12月1日發表在《細胞—代謝》雜誌上。
研究人員表示，類風溼關節炎（RA）中的自身免疫性T細胞在線粒體耗氧量和ATP產生方面存在缺陷。
研究人員發現，抑制琥珀酸-CoA連接酶（SUCLG2）的GDP形成β亞基是潛在的異常。缺乏SUCLG2的T細胞將三羧酸（TCA）循環從氧化方向改變為還原方向，積累了α-酮戊二酸、檸檬酸和乙醯輔酶A（AcCoA），並分化為促炎性效應細胞。在AcCoAhi RA T細胞中，微管蛋白乙醯化作用可穩定微管細胞骨架並將線粒體定位在核周位置，從而導致細胞極化、尾足形成、T細胞遷移和組織浸潤。
在組織中，缺乏SUCLG2的T細胞可作為產生細胞因子的效應細胞發揮功能，並且是過度炎症的，可以通過補充酶來糾正這一缺陷。通過微管蛋白乙醯轉移酶敲低防止T細胞微管蛋白乙醯化足以抑制滑膜炎。這些數據將線粒體衰竭和AcCoA供過於求與自身免疫性組織炎症聯繫起來。
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