气候变化领域集成服务门户(CCPortal): The N-terminal cysteine is a dual sensor of oxygen and oxidative stress

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DOI	10.1073/pnas.2107993118
	The N-terminal cysteine is a dual sensor of oxygen and oxidative stress
	Heo A.J.; Kim S.B.; Ji C.H.; Han D.; Lee S.J.; Lee S.H.; Lee M.J.; Lee J.S.; Ciechanover A.; Kim B.Y.; Kwon Y.T.
发表日期	2021
ISSN	1091-6490
卷号	118 期号:50
英文摘要	Cellular homeostasis requires the sensing of and adaptation to intracellular oxygen (O2) and reactive oxygen species (ROS). The Arg/N-degron pathway targets proteins that bear destabilizing N-terminal residues for degradation by the proteasome or via autophagy. Under normoxic conditions, the N-terminal Cys (Nt-Cys) residues of specific substrates can be oxidized by dioxygenases such as plant cysteine oxidases and cysteamine (2-aminoethanethiol) dioxygenases and arginylated by ATE1 R-transferases to generate Arg-CysO2(H) (R-CO2). Proteins bearing the R-CO2 N-degron are targeted via Lys48 (K48)-linked ubiquitylation by UBR1/UBR2 N-recognins for proteasomal degradation. During acute hypoxia, such proteins are partially stabilized, owing to decreased Nt-Cys oxidation. Here, we show that if hypoxia is prolonged, the Nt-Cys of regulatory proteins can be chemically oxidized by ROS to generate Arg-CysO3(H) (R-CO3), a lysosomal N-degron. The resulting R-CO3 is bound by KCMF1, a N-recognin that induces K63-linked ubiquitylation, followed by K27-linked ubiquitylation by the noncanonical N-recognin UBR4. Autophagic targeting of Cys/N-degron substrates is mediated by the autophagic N-recognin p62/SQTSM-1/Sequestosome-1 through recognition of K27/K63-linked ubiquitin (Ub) chains. This Cys/N-degron-dependent reprogramming in the proteolytic flux is important for cellular homeostasis under both chronic hypoxia and oxidative stress. A small-compound ligand of p62 is cytoprotective under oxidative stress through its ability to accelerate proteolytic flux of K27/K63-ubiquitylated Cys/N-degron substrates. Our results suggest that the Nt-Cys of conditional Cys/N-degron substrates acts as an acceptor of O2 to maintain both O2 and ROS homeostasis and modulates half-lives of substrates through either the proteasome or lysosome by reprogramming of their Ub codes.
英文关键词	Arg/N-degron pathway; Cys/N-degron pathway; N-degron pathway; oxidative stress sensor; oxygen sensor
语种	英语
scopus关键词	guanosine triphosphatase activating protein; interleukin derivative; oxygen; recognins; tumor protein; animal; autophagy; cell line; chemistry; gene expression regulation; genetics; homeostasis; human; metabolism; oxidation reduction reaction; oxidative stress; physiology; Animals; Autophagy; Cell Line; Gene Expression Regulation; GTPase-Activating Proteins; Homeostasis; Humans; Interleukins; Metabolic Networks and Pathways; Neoplasm Proteins; Oxidation-Reduction; Oxidative Stress; Oxygen
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/250929
作者单位	Cellular Degradation Biology Center, College of Medicine, Seoul National UniversitySeoul 03080, South Korea; Department of Biomedical Sciences, College of Medicine, Seoul National UniversitySeoul 03080, South Korea; AUTOTAC Bio Inc., Jongno-guSeoul 03077, South Korea; Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University HospitalSeoul 03082, South Korea; Rappaport Family Technion Integrated Cancer Center, Faculty of Medicine, Technion-Israel Institute of TechnologyHaifa 3109601, Israel; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Korea; yok5@snu.ac.kr; Cellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul 03080, Korea; bykim@kribb.re.kr yok5@snu.ac.kr; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National UniversitySeoul 03080, South Korea
推荐引用方式 GB/T 7714	Heo A.J.,Kim S.B.,Ji C.H.,et al. The N-terminal cysteine is a dual sensor of oxygen and oxidative stress[J],2021,118(50).
APA	Heo A.J..,Kim S.B..,Ji C.H..,Han D..,Lee S.J..,...&Kwon Y.T..(2021).The N-terminal cysteine is a dual sensor of oxygen and oxidative stress.Proceedings of the National Academy of Sciences of the United States of America,118(50).
MLA	Heo A.J.,et al."The N-terminal cysteine is a dual sensor of oxygen and oxidative stress".Proceedings of the National Academy of Sciences of the United States of America 118.50(2021).