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Nat. Commun., Published online:06 October 2016, 7, Article number: 12882 | doi:10.1038/ncomms12882 ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation

Abstract

Ji Hae Seo^1,*, Ji-Hyeon Park^1,*, Eun Ji Lee¹, Tam Thuy Lu Vo¹, Hoon Choi¹, Jun Yong Kim², Jae Kyung Jang¹, Hee-Jun Wee¹, Hye Shin Lee¹, Se Hwan Jang³, Zee Yong Park³, Jaeho Jeong⁴, Kong-Joo Lee⁴, Seung-Hyeon Seok⁵, Jin Young Park⁵, Bong Jin Lee⁵, Mi-Ni Lee⁶, Goo Taeg Oh⁶ & Kyu-Won Kim^1,2,7
¹ SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Korea. ² Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea. ³School of Life Sciences, Gwangju Institute of Science & Technology, Gwangju 61005, Korea. ⁴ Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.⁵The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea. ⁶ Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea. ⁷Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang 25354, Korea.
^* These authors contributed equally to this work.

Correspondence to Kyu-Won Kim.

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.

논문정보

형식Research article
게재일2016년 10월 (BRIC 등록일 2016-10-17)
연구진국내 연구진
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