小柯机器人

研究揭示线粒体应激如何传递至胞质
2020-03-05 12:47

德国路德维希马克西米利安大学Lucas T. Jae研究小组发现,线粒体应激通过DELE1协调途径传递至细胞质。相关论文3月4日在线发表于《自然》。

研究人员将基因组工程和单倍体遗传学结合起来,无偏倚地鉴定了影响C / EBP同源蛋白(CHOP)诱导的基因,C / EBP同源蛋白是线粒体综合应激反应的关键蛋白。

该研究表明,线粒体蛋白酶OMA1和未知蛋白DELE1以及HRI,共同构成了由线粒体应激触发的缺失途径。从机制上讲,应力诱导的OMA1激活会导致DELE1被切割成短肽而聚集在细胞质中,并在胞质通过其C端与HRI结合并激活HRI。根据线粒体紊乱的不同类型,阻断该途径可能是有利的也可能是有弊的。

除了核心途径的组成成分,研究人员通过比较遗传筛选还确定了一组其他调节剂。总的来说,这些发现可用于指导人类在疾病背景下研究细胞对线粒体功能紊乱的响应。

研究人员表示,线粒体保真度与整个细胞内平衡紧密相关,并且在衰老和各种病理过程中受到损害。线粒体功能紊乱需要传递到细胞质中。在哺乳动物细胞中,整合应激反应是由真核翻译起始因子2α(eIF2α)的磷酸化引发的。eIF2α磷酸化由四种eIF2α激酶GCN2、HRI、PERK和PKR介导,它们被多种类型的细胞应激激活。然而,将线粒体紊乱传递到细胞质以触发综合应激反应的机制仍然未知。

附:英文原文

Title: A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol

Author: Evelyn Fessler, Eva-Maria Eckl, Sabine Schmitt, Igor Alves Mancilla, Matthias F. Meyer-Bender, Monika Hanf, Julia Philippou-Massier, Stefan Krebs, Hans Zischka, Lucas T. Jae

Issue&Volume: 2020-03-04

Abstract: Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies1,2,3. Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) in mammalian cells4,5. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress6. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown1,2,7. Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.

DOI: 10.1038/s41586-020-2076-4

Source: https://www.nature.com/articles/s41586-020-2076-4

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


本期文章:《自然》:Online/在线发表

分享到:

0