The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation
The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation
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DOI：
10.1016/j.cmet.2019.06.016
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发表时间：
2019-09-03
期刊：
影响因子：
29
通讯作者：
Weyand, Cornelia M.
中科院分区：
文献类型：
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作者：
Li, Yinyin;Shen, Yi;Weyand, Cornelia M.
在自身免疫性疾病类风湿性关节炎（RA）中，CD 4（+）T细胞通过将葡萄糖从糖酵解和ATP产生中分流出来，促进促炎效应子功能。潜在的机制仍然未知，在这里，我们暗示DNA修复核酸酶MRE 11 A在细胞的生物能量故障。RA T细胞中的MRE 11 A缺陷破坏线粒体氧消耗并抑制ATP产生。此外，MRE 11 A功能丧失导致线粒体泄漏！DNA（mtDNA）进入胞质溶胶，触发炎性小体组装，半胱天冬酶-1激活和细胞死亡。Caspase-1活化在RA患者的淋巴结驻留T细胞中频繁。在体内，MRE 11 A的药理学和遗传学抑制导致mtDNA的组织沉积、半胱天冬酶-1蛋白水解和侵袭性组织炎症。相反，MRE 11 A过表达恢复了线粒体！健身和保护组织免受炎症攻击。因此，核酸酶MRE 11 A调节线粒体保护程序，并且MRE 11 A缺陷导致DNA修复缺陷、能量产生以及组织稳态的失败和丧失。
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 mitochondria! 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 mitochondria! fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondria, protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.