Proteomic Analysis of Lysine Acetylation Sites in Rat Tissues Reveals Organ Specificity and Subcellular Patterns

Novo Nordisk Foundation Center for Protein Research, Department for Proteomics, Faculty of Health Sciences, University of Copenhagen, Denmark.
Cell Reports (Impact Factor: 8.36). 08/2012; 2(2):419-31. DOI: 10.1016/j.celrep.2012.07.006
Source: PubMed


Lysine acetylation is a major posttranslational modification involved in a broad array of physiological functions. Here, we provide an organ-wide map of lysine acetylation sites from 16 rat tissues analyzed by high-resolution tandem mass spectrometry. We quantify 15,474 modification sites on 4,541 proteins and provide the data set as a web-based database. We demonstrate that lysine acetylation displays site-specific sequence motifs that diverge between cellular compartments, with a significant fraction of nuclear sites conforming to the consensus motifs G-AcK and AcK-P. Our data set reveals that the subcellular acetylation distribution is tissue-type dependent and that acetylation targets tissue-specific pathways involved in fundamental physiological processes. We compare lysine acetylation patterns for rat as well as human skeletal muscle biopsies and demonstrate its general involvement in muscle contraction. Furthermore, we illustrate that acetylation of fructose-bisphosphate aldolase and glycerol-3-phosphate dehydrogenase serves as a cellular mechanism to switch off enzymatic activity.

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Available from: Alicia Lundby,
    • "This may contribute to the elevated variability in lysine acetylation patterns encountered in organs and subcellular fractions in distinct functional states (Lundby et al., 2012). Here, we discuss the ability of acetyl-CoA to regulate adaptive responses to homeostatic perturbations by controlling the equilibrium between catabolic and anabolic reactions as well as by influencing major cellular processes such as cell cycle progression , mitosis, autophagy, and regulated cell death (RCD). "
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    ABSTRACT: Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; 21(6):805-821. DOI:10.1016/j.cmet.2015.05.014 · 17.57 Impact Factor
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    • "Overall, however, there are clearly more questions than answers. One major issue in extrapolating to skeletal muscle is that many of the to-date identified Ac-Lys residues in the insulin signaling pathway (but not glucose metabolism ) were not identified in human skeletal muscle (Choudhary et al., 2009; Lundby et al., 2012). Part of the reason for this could be that the muscle tissue was not insulin-stimulated, which might limit overall coverage. "
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    ABSTRACT: Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging. If potential treatments are to be developed to treat insulin resistance, then it is important to fully understand insulin signaling and glucose metabolism. While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood. In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.
    Moleculer Cells 03/2015; 38(4). DOI:10.14348/molcells.2015.0020 · 2.09 Impact Factor
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    • "We and others have previously discovered that lysine acetylation is an evolutionarily conserved post-translational modification in the regulation of a wide range of cellular processes, particularly in nuclear transcription and cytoplasmic metabolism (Kim et al, 2006; Choudhary et al, 2009; Zhao et al, 2010). To date, more than 4,500 acetylated proteins have been identified (Lundby et al, 2012). Among these acetylated proteins is MDH2, in which as many as four lysine residues are acetylated, and acetylation has been shown to activate MDH2 (Zhao et al, 2010). "
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    ABSTRACT: The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD(+) redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate-aspartate NADH shuttle activity and oxidative protection. © 2015 The Authors.
    The EMBO Journal 03/2015; 34(8). DOI:10.15252/embj.201591041 · 10.43 Impact Factor
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