한빛사 논문
Gregory C. Addicks1*, Hongbo Zhang2,3*, Dongryeol Ryu4*, Goutham Vasam1, Alexander E. Green1,5, Philip L. Marshall1, Sonia Patel1, Baeki E. Kang4, Doyoun Kim6, Elena Katsyuba3, Evan G. Williams7, Jean-Marc Renaud8, Johan Auwerx3, and Keir J. Menzies1,5
1Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; 2Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; 3Laboratory of Integrative Systems Physiology, Ecole polytechnique federale de Lausanne, Lausanne, Switzerland; 4Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea; 5Ottawa Institute of Systems Biology and the Eric Poulin Centre for Neuromuscular Disease, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 6Division of Therapeutics and Biotechnology, Korea Research Institute of Chemical Technology, Daejeon, South Korea; 7Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; 8Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
*G.C. Addicks, H. Zhang, and D. Ryu contributed equally to this paper;
Correspondence to Keir J. Menzies; Johan Auwerx.
Abstract
Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.
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