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研究揭示线粒体应激信号传递通路
作者:小柯机器人 发布时间:2020/3/9 12:26:18

美国加利福尼亚大学Martin Kampmann研究组发现线粒体应激通过OMA1-DELE1-HRI途径传递至细胞质。相关论文于202034日发表在《自然》杂志上。

他们表明HRI是线粒体应激传递到ATF4必要和充分的真核翻译起始因子eIF2α)激酶。在全基因组的CRISPR干扰筛选过程中,他们确定了HRI上游的因子:OMA1,一种线粒体应激激活的蛋白酶;和DELE1,他们发现的一种与线粒体内膜有关特征很少的蛋白。线粒体应激刺激OMA1依赖的DELE1裂解,并导致DELE1在细胞质中积累,在细胞质中与HRI相互作用并激活HRIeIF2α激酶活性。此外,DELE1eIF2α磷酸化下游的ATF4翻译所需的。OMA1-DELE1-HRI途径的阻断触发了某种反应,并诱导了特定的分子伴侣。因此,OMA1-DELE1-HRI途径代表了潜在的治疗靶标,可以使涉及线粒体功能障碍的疾病的整体预后微调。

据悉,在哺乳动物细胞中,线粒体功能障碍触发了整体应激反应,其中eIF2α的磷酸化诱导转录因子ATF4。但是,线粒体应激如何传递到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

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html