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Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity

ISSN号：0253-3820
期刊名称：《分析化学》
时间：0
分类：Q51[生物学—生物化学] O636.1[理学—高分子化学;理学—化学]
作者机构：[1]State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China, [2]High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China, [3]Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, [4]Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
相关基金：This work was supported by grants from the National Natural Sci- ence Foundation of China （Grant Nos. 91313302, 31171334, and 31170782） and the Tianjin Natural Science Foundation （11JCYBJC25500）. L.Z. performed most of the experiments. S.L. and Y.Z. carried out proteomics experiments and bioinformatics analysis. L.Z., S.L., N.L., M.L., D.L., and W.S. analyzed data. E.S. gave important suggestions about the research strategy. T.-P.Y. provided HDAC6 knockout mice. L.Z., S.L., W.S., and J.Z. wrote the manuscript. W.S. and J.Z. con- ceived and designed experiments.

作者： Linlin Zhang[1], Shanshan Liu[1,2], Ningning Liu[1], Yong Zhang[1,2], Min Liu[1], Dengwen Li[1], Edward Seto[3], Tso-PangYao[4], Wenqing Shui[1,2], J-un Zhou[1]

关键词：蛋白质组学, 脱乙酰基, 酶活性, 功能特性, 基板, 鉴定, 小说, 肌球蛋白重链, HDAC6, substrate, lysine acetylation,quantitative proteomics, interaction

中文摘要：

Histone deacetylase 6 (HDAC6 ) ，主要细胞质的蛋白质 deacetylase，通过它的 deacetylase 活动参予大量细胞的过程。然而， HDAC6 的多样的功能不能充分与它的已知的底层被阐明。在一次尝试到探索 HDAC6 的底层差异，我们执行了量的 proteomic 分析响应 HDAC6 在许多蛋白质离氨酸 acetylation 监视变化缺乏。我们在 HDAC6 猛烈老鼠的肝与提高的 acetylation 识别了 107 蛋白质。三细胞质的蛋白质，包括肌浆球蛋白重链 9 (MYH9 ) ，热吃惊血缘的蛋白质 70 (Hsc70 ) ，并且 dnaJ 相当或相同的事物亚科 A 成员 1 (DNAJA1 ) ，被验证与 HDAC6 交往。这些蛋白质的 acetylation 层次被 HDAC6 否定地在老鼠肝并且在有教养的房间调整。功能的研究表明调停 HDAC6 的 deacetylation 调制在 Hsc70 和 DNAJA1 之间的 MYH9 和相互作用的肌动朊绑定能力。这些调查结果巩固 HDAC6 以协调各种各样的细胞的功能的能力作为蛋白质 acetylation 的一个批评管理者供给的观点。

英文摘要：

Histone deacetylase 6 （HDAC6）, a predominantly cyto- plasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 can- not be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 （MYH9）, heat shock cognate pro- tein 70 （HscT0）, and dnaJ homolog subfamily A member 1 （DNAJA1）, were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6- mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of proteinacetylation with the capability of coordinating various cellular functions.