title: A redox mechanism underlying nucleolar stress sensing by nucleophosmin.
abstract: The nucleolus has been recently described as a stress sensor. The nucleoplasmic translocation of nucleolar protein nucleophosmin (NPM1) is a hallmark of nucleolar stress; however, the causes of this translocation and its connection to p53 activation are unclear. Using single live-cell imaging and the redox biosensors, we demonstrate that nucleolar oxidation is a general response to various cellular stresses. During nucleolar oxidation, NPM1 undergoes S-glutathionylation on cysteine 275, which triggers the dissociation of NPM1 from nucleolar nucleic acids. The C275S mutant NPM1, unable to be glutathionylated, remains in the nucleolus under nucleolar stress. Compared with wild-type NPM1 that can disrupt the p53-HDM2 interaction, the C275S mutant greatly compromises the activation of p53, highlighting that nucleoplasmic translocation of NPM1 is a prerequisite for stress-induced activation of p53. This study elucidates a redox mechanism for the nucleolar stress sensing and may help the development of therapeutic strategies.
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Xuxu
authors.initials: X
authors.lastname: Sun
authors.affiliation: Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Yi
authors.identifier: 0000-0001-7896-1184
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors.forename: Xie
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230022, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005978:Glutathione