研究揭示DNA修覆核酸酶MER11A新功能
作者：
小柯機器人發布時間：2019/9/4 16:24:29
美國史丹福大學醫學院Cornelia M. Weyand研究組發現DNA修覆核酸酶MRE11A可參與保護線粒體並防止T細胞焦亡與組織炎症。這一研究成果發表在2019年9月3日出版的國際學術期刊《細胞—代謝》上。
據研究人員介紹，在自身免疫性疾病類風溼性關節炎（RA）中，CD4 陽性T細胞通過將葡萄糖分流遠離糖酵解和ATP產生來促進促炎效應子功能。
這其中潛在的機制仍然未知，研究人員發現DNA修覆核酸酶MRE11A在細胞的生物能量衰竭中有作用。RA T細胞中的MRE11A缺乏破壞了線粒體氧消耗並抑制了ATP的產生。此外，MRE11A功能喪失導致線粒體DNA（mtDNA）洩漏到胞質中，從而引發炎性小體組裝、caspase-1活化和細胞焦亡。RA患者的淋巴結駐留T細胞中caspase-1活化頻繁。在體內，MRE11A的藥理和遺傳抑制導致mtDNA的組織沉積、caspase-1蛋白水解和侵襲性組織炎症。相反，MRE11A過表達可恢復線粒體適應性並使得組織免受炎症發作。因此，核酸酶MRE11A調節線粒體保護程序，並且MRE11A缺乏導致DNA修復缺陷、能量產生以及組織穩態喪失。
附：英文原文
Title: The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation
Author: Jorg J. Goronzy, Cornelia M. Weyand, et al
Issue&Volume: Volume 30 Issue 3
Abstract: In the autoimmune disease rheumatoid arthritis (RA), CD4 + T cells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells』 bioenergetic failure. MRE11A deficiency in RA T cells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing T cells in RA patients. In vivo, pharmacologic and genetic inhibition of MRE11A resulted in tissue deposition of mtDNA, caspase-1 proteolysis, and aggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.
DOI: https://doi.org/10.1016/j.cmet.2019.06.016
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30319-5