title: Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity.
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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Dengwen
authors.initials: D
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Wenqing
authors.initials: W
authors.lastname: Shui
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000107:Acetylation; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D007553:Isotope Labeling; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018995:Myosin Heavy Chains; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D000199:Actins; C494639:Dnaja1 protein, mouse; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; C525088:Myh9 protein, mouse; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains; D008239:Lysine