title: Identification of an adaptor protein that facilitates Nrf2-Keap1 complex formation and modulates antioxidant response.
abstract: Nrf2 plays a key role in the protection of the body against environmental stress via inducible expression of detoxification and antioxidant enzymes. Keap1 functions as a sensor for oxidative and electrophilic stresses and promotes Nrf2 degradation via its E3 ligase activity. Modulation of the Nrf2-Keap1 pathway has been extensively explored as a strategy to combat against drug toxicity and stress-induced diseases. Here we report a new player that modulates the Nrf2-Keap1 pathway. PAQR3, a membrane protein specifically localized in the Golgi apparatus, negatively regulates the expression of an array of Nrf2 target genes and alters cellular level of reactive oxygen species. PAQR3 tethers Nrf2 and Keap1, but not small MAF proteins to the Golgi apparatus. PAQR3 interacts with both Nrf2 and Keap1 and facilitates the interaction of Nrf2 with Keap1. PAQR3 promotes ubiquitination and degradation of Nrf2. Disruption of PAQR3 interaction with Nrf2 and Keap1 by a synthetic peptide reduces Nrf2 ubiquitination and elevates expression of Nrf2 target genes. At the animal level, deletion of PAQR3 increases Nrf2 protein level and the expression of Nrf2 target genes. In conclusion, our study pinpoints that PAQR3 functions as an adaptor protein to promote Nrf2-Keap1 complex formation, thereby modulating the Nrf2-Keap2 pathway and playing an important role in controlling antioxidant response of the cell.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yuxue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yongfan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chunchun
authors.initials: C
authors.lastname: Liu
authors.affiliation: The National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai 200336, China.
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute of Biomedical and Pharmaceutical Technology, Fuzhou University, Fuzhou 350002, China.
authors.forename: Jiu-Lin
authors.initials: JL
authors.lastname: Wu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Daqian
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Xue
authors.initials: X
authors.lastname: You
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: ychen3@sibs.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C532354:PAQR3 protein, human; D017382:Reactive Oxygen Species
keywords: Antioxidant; Golgi apparatus; Keap1; Nrf2; PAQR3; Ubiquitination