ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation

Ji Hae Seo, Ji-Hyeon Park, Eun Ji Lee, Tam Thuy Lu Vo, Hoon Choi, Jun Yong Kim, Jae Kyung Jang, Hee-Jun Wee, Hye Shin Lee, Se Hwan Jang, Zee Yong Park, Jaeho Jeong, Kong-Joo Lee, Seung-Hyeon Seok, Jin Young Park, Bong Jin Lee, Mi-Ni Lee, Goo Taeg Oh and Kyu-Won Kim ()
Additional contact information
Ji Hae Seo: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Ji-Hyeon Park: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Eun Ji Lee: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Tam Thuy Lu Vo: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Hoon Choi: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Jun Yong Kim: Graduate School of Convergence Science and Technology, Seoul National University
Jae Kyung Jang: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Hee-Jun Wee: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Hye Shin Lee: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University
Se Hwan Jang: School of Life Sciences, Gwangju Institute of Science & Technology
Zee Yong Park: School of Life Sciences, Gwangju Institute of Science & Technology
Jaeho Jeong: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University
Kong-Joo Lee: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University
Seung-Hyeon Seok: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University
Jin Young Park: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University
Bong Jin Lee: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University
Mi-Ni Lee: Ewha Womans University
Goo Taeg Oh: Ewha Womans University
Kyu-Won Kim: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12882

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