Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity |
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Authors: | Linlin Zhang Shanshan Liu Ningning Liu Yong Zhang Min Liu Dengwen Li Edward Seto Tso-Pang Yao Wenqing Shui Jun Zhou |
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Institution: | 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China2. High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin 300457, China3. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA4. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA |
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Abstract: | Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot 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 protein 70 (Hsc70), 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 protein acetylation with the capability of coordinating various cellular functions. |
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Keywords: | HDAC6 substrate lysine acetylation quantitative proteomics interaction |
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