title: ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation.
abstract: Heat shock protein (Hsp)70 is a molecular chaperone that maintains protein homoeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. However, the mechanisms by which Hsp70 balances these opposing functions under stress conditions remain unknown. Here, we demonstrate that Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation. During the early stress response, Hsp70 is immediately acetylated by ARD1 at K77, and the acetylated Hsp70 binds to the co-chaperone Hop to allow protein refolding. Thereafter, Hsp70 is deacetylated and binds to the ubiquitin ligase protein CHIP to complete protein degradation during later stages. This switch is required for the maintenance of protein homoeostasis and ultimately rescues cells from stress-induced cell death in vitro and in vivo. Therefore, ARD1-mediated Hsp70 acetylation is a regulatory mechanism that temporally balances protein refolding/degradation in response to stress.
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Tam Thuy Lu
authors.initials: TT
authors.lastname: Vo
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Kim
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Jang
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Wee
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Hye Shin
authors.initials: HS
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science &Technology, Gwangju 61005, Korea.
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Jang
authors.affiliation: School of Life Sciences, Gwangju Institute of Science &Technology, Gwangju 61005, Korea.
authors.forename: Zee Yong
authors.initials: ZY
authors.lastname: Park
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.
authors.forename: Jaeho
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.
authors.forename: Kong-Joo
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Seung-Hyeon
authors.initials: SH
authors.lastname: Seok
authors.affiliation: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
authors.forename: Bong Jin
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea.
authors.forename: Mi-Ni
authors.initials: MN
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea.
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea.|Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang 25354, Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D049452:Green Fluorescent Proteins / Q000737:chemistry; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry; D009154:Mutation; D063209:N-Terminal Acetyltransferase A / Q000378:metabolism*; D063213:N-Terminal Acetyltransferase E / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D058849:Protein Refolding; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological; D015027:Zebrafish
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; D020169:Caspases