Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response
Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response
复制标题
DOI：
10.1096/fj.11-193706
复制
发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Chinnaiyan, Prakash
中科院分区：
文献类型：
--
作者：
Kahali, Soumen;Sarcar, Bhaswati;Chinnaiyan, Prakash
通过蛋白质乙酰化进行的翻译后修饰正在成为细胞调节的重要模式。我们之前已经证明了葡萄糖调节蛋白 78 kDa (GRP78) 乙酰化和随后的未折叠蛋白反应 (UPR) 激活在 I 类组蛋白脱乙酰酶 (HDAC) 抑制剂的抗肿瘤活性中发挥的作用，该抑制剂主要针对 I 类 HDAC。在这项研究中，我们探讨了这些 I 类 HDAC 在 UPR 调节中可能发挥的贡献作用。使用 HA 标记的 GRP78 和 FLAG 标记的 HDAC 双转染后，使用免疫沉淀/免疫印迹进行结合研究。使用分级细胞裂解物的蛋白质印迹和共聚焦显微镜进行亚细胞定位。使用 RNA 干扰抑制单个 HDAC。我们确定了 HDAC 1、2 和 3 与 GRP78 结合的潜力。这些 HDAC 与内质网 (ER) 中的 GRP78 共定位。抑制单个 HDAC 会导致 GRP78 乙酰化和 UPR 选择性激活。虽然传统上将其视为核酶，但我们证明 I 类 HDAC 定位于 ER，与 GRP78 结合，并选择性激活 UPR，代表了一种新的 UPR 调节模式和 HDAC 抑制剂的作用机制。-Kahali, S.、Sarcar, B.、Prabhu, A.、Seto, E.、Chinnaiyan, P。I 类组蛋白脱乙酰酶定位于内质网并调节未折叠蛋白回应。 FASEB J. 26, 2437-2445 (2012)。 www.fasebj.org
Post-translational modification through protein acetylation is emerging as an important mode of cellular regulation. We have previously demonstrated the role that glucose-regulated protein 78 kDa (GRP78) acetylation and subsequent activation of the unfolded protein response (UPR) play in the antitumor activity of class I histone deacetylase (HDAC) inhibitors, which primarily target class I HDACs. In this study, we explored the contributory role these class I HDACs may play in UPR regulation. Binding studies were performed using immunoprecipitation/immunoblotting following dual-transfection with HA-tagged GRP78 and FLAG-tagged HDACs. Subcellular localization was performed using Western blot of fractionated cell lysates and confocal microscopy. Individual HDACs were inhibited using RNA interference. We identified the potential of HDACs 1, 2, and 3 to bind to GRP78. These HDACs colocalized with GRP78 in the endoplasmic reticulum (ER). Inhibition of individual HDACs resulted in GRP78 acetylation and selective activation of the UPR. Although traditionally viewed as nuclear enzymes, we demonstrate that Class I HDACs localize to the ER, bind to GRP78, and selectively activate the UPR, representing a novel mode of UPR regulation and mechanism of action of HDAC inhibitors.-Kahali, S., Sarcar, B., Prabhu, A., Seto, E., Chinnaiyan, P. Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response. FASEB J. 26, 2437-2445 (2012). www.fasebj.org