title: PP2A-AMPKα-HSF1 axis regulates the metal-inducible expression of HSPs and ROS clearance.
abstract: Metals such as cadmium and arsenic are ubiquitous toxicants that cause a variety of adverse health effects. Heat shock proteins (HSPs) response to metal-induced stress and protect cells from further damage. However, the intracellular signalling pathways responsible for activation of HSPs expression are not fully understood. Here, we demonstrate that protein phosphatase 2A (PP2A) regulates expression of HSP70 and HSP27 via dephosphorylation of an AMP-activated protein kinase α subunit (AMPKα) at Thr172. Dephosphorylated AMPKα phosphorylates heat shock factor 1 (HSF1) at Ser303, leading to significant transcriptional suppression of HSP70 and HSP27 in CdCl2- or NaAsO2-treated cells. Suppression of PP2A regulatory B56δ subunit resulted in the sustained phosphorylation of AMPKα upon CdCl2 treatment, subsequent reduction in expression of HSP70 and HSP27, and thereby dramatic reduction of reactive oxygen species (ROS) clearance. We further revealed that PP2A B56δ physically interacted with AMPKα, providing evidence that PP2A B56δ-AMPKα-HSF1 signalling pathway participated in regulating the inducible expression of HSPs and ROS clearance. Taken together, we identified a novel PP2A-dependent signalling pathway involved in regulation of HSPs expression in response to metal stress.
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiao-nian
authors.initials: XN
authors.lastname: Zhu
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Li-ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Bai
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Dao-chuan
authors.initials: DC
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jin-miao
authors.initials: JM
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zi-ning
authors.initials: ZN
authors.lastname: Lei
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zheng-bao
authors.initials: ZB
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiu-mei
authors.initials: XM
authors.lastname: Xing
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Cai-xia
authors.initials: CX
authors.lastname: Liu
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zhi-ni
authors.initials: ZN
authors.lastname: He
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yong-mei
authors.initials: YM
authors.lastname: Xiao
authors.affiliation: School of Public Health, Guiyang Medical University, Guiyang 550004, China.
authors.forename: Ai-hua
authors.initials: AH
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: zengxw123@163.com.
authors.forename: Xiao-wen
authors.initials: XW
authors.lastname: Zeng
authors.affiliation: Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: chenwen@mail.sysu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity; D002104:Cadmium / Q000633:toxicity; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008670:Metals / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D008670:Metals; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D002104:Cadmium; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D054648:Protein Phosphatase 2; D001151:Arsenic
keywords: AMPKα; Heat shock proteins; Heat shock transcription factor 1; Oxidative damage; Protein phosphatase 2A B56δ subunit