Ryu Hyun-Wook, Won Hye-Rim, Lee Dong Hoon, Kwon So Hee
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, 03722, Republic of Korea.
Cell Stress Chaperones. 2017 Mar;22(2):253-261. doi: 10.1007/s12192-017-0763-3. Epub 2017 Jan 23.
Histone deacetylase 6 (HDAC6) plays an important role in stress responses such as misfolded protein-induced aggresomes, autophagy, and stress granules. However, precisely how HDAC6 manages response during and after cellular stress remains largely unknown. This study aimed to investigate the effect of HDAC6 on various stress and post-stress recovery responses. We showed that HIF-1α protein levels were reduced in HDAC6 knockout (KO) MEFs compared to wild-type (WT) MEFs in hypoxia. Furthermore, under hypoxia, HIF-1α levels were also reduced following rescue with either a catalytically inactive or a ubiqiutin-binding mutant HDAC6. HDAC6 deacetylated and upregulated the stability of HIF-1α, leading to activation of HIF-1α function under hypoxia. Notably, both the deacetylase and ubiquitin-binding activities of HDAC6 contributed to HIF-1α stabilization, but only deacetylase activity was required for HIF-1α transcriptional activity. Suppression of HDAC6 enhanced the interaction between HIF-1α and HSP70 under hypoxic conditions. In addition to hypoxia, depletion of HDAC6 caused hypersensitivity to cell death during oxidative stress and post-stress recovery. However, HDAC6 depletion had no effect on cell death in response to heat shock or ionizing radiation. Overall, our data suggest that HDAC6 may serve as a critical stress regulator in response to different cellular stresses.
组蛋白去乙酰化酶6（HDAC6）在诸如错误折叠蛋白诱导的聚集体、自噬和应激颗粒等应激反应中发挥重要作用。然而，HDAC6在细胞应激期间及之后究竟如何调控反应仍 largely未知。本研究旨在探究HDAC6对各种应激及应激后恢复反应的影响。我们发现，与野生型（WT）MEF相比，在缺氧条件下，HDAC6基因敲除（KO）的MEF中HIF-1α蛋白水平降低。此外，在缺氧条件下，用催化失活的或泛素结合突变体HDAC6进行挽救后，HIF-1α水平也降低。HDAC6使HIF-1α去乙酰化并上调其稳定性，从而在缺氧条件下激活HIF-1α功能。值得注意的是，HDAC6的去乙酰化酶和泛素结合活性均有助于HIF-1α的稳定，但只有去乙酰化酶活性是HIF-1α转录活性所必需的。在缺氧条件下，抑制HDAC6增强了HIF-1α与HSP70之间的相互作用。除了缺氧，HDAC6的缺失在氧化应激及应激后恢复期间导致对细胞死亡的超敏反应。然而，HDAC6的缺失对热休克或电离辐射诱导的细胞死亡没有影响。总体而言，我们的数据表明HDAC6可能作为一种关键的应激调节因子来应对不同的细胞应激。
