Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway

doi:10.1038/s41586-020-2078-2

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2078-2
	Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway
	Moral, John Alec 1,2,3; Leung, Joanne 1,2,3; Rojas, Luis A.1,2,3; Ruan, Jennifer 1,2,3; Zhao, Julia 1,2,3; Sethna, Zachary 1,2,3; Ramnarain, Anita 1,2,3; Gasmi, Billel 4; Gururajan, Murali 5; Redmond, David 6; Askan, Gokce 7; Bhanot, Umesh 7; Elyada, Ela 8,9; Park, Youngkyu 8,9; Tuveson, David A.8,9
	2020-02-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	USA
英文关键词	In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) results in the induction of the transcription factor ATF4(1-3). However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2 alpha 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 eIF2 alpha kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2 alpha 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. A genome-wide CRISPR interference screen shows that a signalling pathway involving OMA1, DELE1 and the eIF2 alpha kinase HRI relays mitochondrial stress to the cytosol to trigger the integrated stress response.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000518098200003
WOS关键词	UNFOLDED PROTEIN RESPONSE ; FACTOR 2-ALPHA KINASE ; INITIATION ; METABOLISM ; PLATFORM ; CRISPR ; INHIBITION ; DISEASES ; DEFICITS
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281351
专题	地球科学资源环境科学气候变化
作者单位	1.Mem Sloan Kettering Canc Ctr, Dept Surg, Hepatopancreatobiliary Serv, 1275 York Ave, New York, NY 10021 USA; 2.Mem Sloan Kettering Canc Ctr, Parker Inst Canc Immunotherapy, 1275 York Ave, New York, NY 10021 USA; 3.Mem Sloan Kettering Canc Ctr, David M Rubenstein Ctr Pancreat Canc Res, 1275 York Ave, New York, NY 10021 USA; 4.Mem Sloan Kettering Canc Ctr, Swim Amer Ludwig Collaborat Lab, 1275 York Ave, New York, NY 10021 USA; 5.Bristol Myers Squibb Co, Immunooncol Biol, Princeton, NJ USA; 6.Weill Cornell Med, Dept Med, Div Regenerat Med, Ansary Stem Cell Inst, New York, NY USA; 7.Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA; 8.Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA; 9.Lustgarten Fdn Pancreat Canc Res Lab, Cold Spring Harbor, NY USA; 10.Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10021 USA; 11.Dartmouth Norris Cotton Canc Ctr, Lebanon, NH USA; 12.Mem Sloan Kettering Canc Ctr, Dept Med, Melanoma & Immunotherapeut Serv, 1275 York Ave, New York, NY 10021 USA; 13.Cornell Univ, Weill Cornell Med Coll, New York, NY 10065 USA; 14.Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA; 15.Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA; 16.Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA
推荐引用方式 GB/T 7714	Moral, John Alec,Leung, Joanne,Rojas, Luis A.,et al. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway[J]. NATURE,2020.
APA	Moral, John Alec.,Leung, Joanne.,Rojas, Luis A..,Ruan, Jennifer.,Zhao, Julia.,...&Tuveson, David A..(2020).Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.NATURE.
MLA	Moral, John Alec,et al."Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway".NATURE (2020).