气候变化领域集成服务门户(CCPortal): Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction

CCPortal

DOI	10.1073/pnas.2022120118
	Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction
	Condon K.J.; Orozco J.M.; Adelmann C.H.; Spinelli J.B.; van der Helm P.W.; Roberts J.M.; Kunchok T.; Sabatini D.M.
发表日期	2021
ISSN	00278424
卷号	118 期号:4
英文摘要	In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity, including DCAF7, CSNK2B, SRSF2, IRS4, CCDC43, and HSD17B10. Using the genome-wide screening data, we generated a focused sublibrary containing single guide RNAs (sgRNAs) targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. While it is well appreciated that mitochondria signal to mTORC1, the mechanisms are not completely clear. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CRISPR-Cas9 screen; Mitochondria; MTORC1
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180849
作者单位	Whitehead Institute for Biomedical Research, Cambridge, MA 02142, United States; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, United States; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, United States; Broad Institute of Harvard, Massachusetts Institute of Technology, Cambridge, MA 02142, United States
推荐引用方式 GB/T 7714	Condon K.J.,Orozco J.M.,Adelmann C.H.,et al. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction[J],2021,118(4).
APA	Condon K.J..,Orozco J.M..,Adelmann C.H..,Spinelli J.B..,van der Helm P.W..,...&Sabatini D.M..(2021).Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction.Proceedings of the National Academy of Sciences of the United States of America,118(4).
MLA	Condon K.J.,et al."Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction".Proceedings of the National Academy of Sciences of the United States of America 118.4(2021).