研究揭示線粒體應激信號傳遞通路
作者：
小柯機器人發布時間：2020/3/9 12:26:18
美國加利福尼亞大學Martin Kampmann研究組發現線粒體應激通過OMA1-DELE1-HRI途徑傳遞至細胞質。相關論文於2020年3月4日發表在《自然》雜誌上。
他們表明HRI是線粒體應激傳遞到ATF4必要和充分的真核翻譯起始因子2α（eIF2α）激酶。在全基因組的CRISPR幹擾篩選過程中，他們確定了HRI上遊的因子：OMA1，一種線粒體應激激活的蛋白酶；和DELE1，他們發現的一種與線粒體內膜有關特徵很少的蛋白。線粒體應激刺激OMA1依賴的DELE1裂解，並導致DELE1在細胞質中積累，在細胞質中與HRI相互作用並激活HRI的eIF2α激酶活性。此外，DELE1是eIF2α磷酸化下遊的ATF4翻譯所需的。OMA1-DELE1-HRI途徑的阻斷觸發了某種反應，並誘導了特定的分子伴侶。因此，OMA1-DELE1-HRI途徑代表了潛在的治療靶標，可以使涉及線粒體功能障礙的疾病的整體預後微調。
據悉，在哺乳動物細胞中，線粒體功能障礙觸發了整體應激反應，其中eIF2α的磷酸化誘導轉錄因子ATF4。但是，線粒體應激如何傳遞到ATF4尚不清楚。
附：英文原文
Title: Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway
Author: Xiaoyan Guo, Giovanni Aviles, Yi Liu, Ruilin Tian, Bret A. Unger, Yu-Hsiu T. Lin, Arun P. Wiita, Ke Xu, M. Almira Correia, Martin Kampmann
Issue&Volume: 2020-03-04
Abstract: In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF41,2,3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blockade of the OMA1–DELE1–HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1–DELE1–HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction.
DOI: 10.1038/s41586-020-2078-2
Source: https://www.nature.com/articles/s41586-020-2078-2