SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways

Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates subject to these modifications is unknown. We report systematic profiling of the mammalian succinylo...

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Bibliographic Details
Published in:Molecular cell Vol. 50; no. 6; p. 919
Main Authors: Park, Jeongsoon, Chen, Yue, Tishkoff, Daniel X, Peng, Chao, Tan, Minjia, Dai, Lunzhai, Xie, Zhongyu, Zhang, Yi, Zwaans, Bernadette M M, Skinner, Mary E, Lombard, David B, Zhao, Yingming
Format: Journal Article
Language:English
Published: United States 27.06.2013
Subjects:
Acetylation
Amino Acid Sequence
Animals
Cell Respiration
Cells, Cultured
Consensus Sequence
Glycosylation
Kinetics
Lysine - metabolism
Metabolic Networks and Pathways
Mice
Mice, Knockout
Mitochondria - enzymology
Molecular Sequence Annotation
Protein Interaction Maps
Protein Processing, Post-Translational
Protein Transport
Proteome - metabolism
Pyruvate Dehydrogenase Complex - metabolism
Sirtuins - genetics
Sirtuins - metabolism
Succinate Dehydrogenase - metabolism
ISSN:1097-4164, 1097-4164
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Summary:Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates subject to these modifications is unknown. We report systematic profiling of the mammalian succinylome, identifying 2,565 succinylation sites on 779 proteins. Most of these do not overlap with acetylation sites, suggesting differential regulation of succinylation and acetylation. Our analysis reveals potential impacts of lysine succinylation on enzymes involved in mitochondrial metabolism; e.g., amino acid degradation, the tricarboxylic acid cycle (TCA) cycle, and fatty acid metabolism. Lysine succinylation is also present on cytosolic and nuclear proteins; indeed, we show that a substantial fraction of SIRT5 is extramitochondrial. SIRT5 represses biochemical activity of, and cellular respiration through, two protein complexes identified in our analysis, pyruvate dehydrogenase complex and succinate dehydrogenase. Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2013.06.001