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.
Nat Commun. 2016 Oct 6;7:12882. doi: 10.1038/ncomms12882.
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.
热休克蛋白 70（Hsp70）是一种分子伴侣，通过两种相反的机制在细胞应激时维持蛋白质的同型平衡：蛋白质重折叠和降解。然而，在应激条件下，Hsp70 如何平衡这些相反的功能的机制尚不清楚。在这里，我们证明 Hsp70 在应激后优先促进蛋白质重折叠，通过一种依赖于 ARD1 介导的 Hsp70 乙酰化的机制逐渐转向蛋白质降解。在早期应激反应中，Hsp70 立即被 ARD1 在 K77 处乙酰化，乙酰化的 Hsp70 与共伴侣 Hop 结合以允许蛋白质重折叠。此后，Hsp70 去乙酰化并与泛素连接酶蛋白 CHIP 结合，在后期完成蛋白质降解。这种转换对于维持蛋白质同型平衡至关重要，最终可挽救体外和体内应激诱导的细胞死亡。因此，ARD1 介导的 Hsp70 乙酰化是一种调节机制，可根据应激情况适时平衡蛋白质的重折叠/降解。
