Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition
Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition
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DOI：
10.1016/j.freeradbiomed.2012.09.023
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发表时间：
2012-12-01
影响因子：
7.4
通讯作者：
Grune, Tilman
中科院分区：
文献类型：
--
作者：
Kaestle, Marc;Woschee, Esther;Grune, Tilman
蛋白酶体负责多泛素化蛋白的降解。抑制蛋白酶体会导致多泛素化蛋白的积累，从而破坏细胞蛋白质的动态平衡。为了防止蛋白酶体抑制对细胞的损害，有几种热休克蛋白(HSPs)的上调，包括HSP27。HSP70和血红素加氧酶-1(HO-1)。研究表明，HSP27和HSP70等经典HSPs的诱导依赖于HDAC6依赖的机制，该机制释放HSF-1并诱导新合成的HSPs的表达。在本研究中，我们证明了HO-1对蛋白酶体抑制的上调是由p38MAPK和NRF-2介导的。有趣的是，我们发现了更多的证据，证明HDAC6参与了HO-1的上调。通过使用针对HDAC6的RNAi技术，我们证明在蛋白酶体抑制后，缺乏预期的HO-1、NRF-2和磷酸化p38(Pp38)的诱导。此外，我们可以证明p38在非应激细胞中是乙酰化的，是HDAC6介导的脱乙酰基的良好底物。因此，我们建议在蛋白酶体抑制时，HDAC6去乙酰化p38，允许随后的p38的磷酸化和最终的NRF-2的激活。NRF-2进入细胞核，作为HO-1的转录因子发挥作用。(C)2012 Elsevier Inc.保留所有权利。
The proteasome is responsible for the degradation of polyubiquitinated proteins. Inhibition of the proteasome leads to an accumulation of polyubiquitinated proteins and thus to an impairment of the cellular protein homeostasis. To prevent cellular damage on proteasome inhibition there is an up-regulation of several heat shock proteins (Hsps), including Hsp27. Hsp70, and heme oxygenase-1 (HO-1). It was demonstrated that the induction of classical Hsps, such as Hsp27 and Hsp70, is dependent on a HDAC6-dependent mechanism which releases HSF-1 and induces the expression of newly synthesized Hsps. In this study we demonstrate that the up-regulation of HO-1 on proteasome inhibition is mediated by p38MAPK and Nrf-2. Interestingly we found additional evidence, proving the involvement of HDAC6 in the upregulation of HO-1. By using RNAi technologies against HDAC6 we demonstrate that there is a lack of the expected induction of HO-1, Nrf-2, and phosphorylated p38 (pp38) after proteasome inhibition. Furthermore, we can show that p38 is acetylated in unstressed cells and is a good substrate for HDAC6-mediated deacetylation. Therefore, we propose that on proteasome inhibition HDAC6 deacetylates p38, allowing the subsequent phosphorylation of p38 and resultant activation of NRF-2. NRF-2 enters the nucleus and functions as a transcription factor for HO-1. (C) 2012 Elsevier Inc. All rights reserved.