Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase

Du, J.; Zhou, Yeyun; Su, Xiaoyang; Yu, Jiu Jiu; Khan, Saba; Jiang, Hong; Kim, Jung-Woo; Woo, Ji-Min; Kim, Jun Huyn; Choi, Brian Hyun; He, Bin; Chen, Wei; Zhang, Sheng; Cerione, Richard A.; Auwerx, Johan; Hao, Quan; Lin, Hening

doi:10.1126/science.1207861

Cited by 1,239 publications

(1,435 citation statements)

References 32 publications

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“…Mutation of Lys199 and Lys242, two established succinylation targets in IDH, decreased enzymatic activity, suggesting that these residues are functionally important and succinylation may affect enzymatic activity. Although the enzyme responsible for succinylation is yet to be identified, a potent desuccinylase (and demalonylase) has been uncovered [34]. Sirt5, another member of the NAD-dependent family of sirtuins, which was previously thought to function primarily as a deacetylase has been shown to have potent desuccinylase activity [34].…”

Section: Reviewmentioning

confidence: 99%

“…Although the enzyme responsible for succinylation is yet to be identified, a potent desuccinylase (and demalonylase) has been uncovered [34]. Sirt5, another member of the NAD-dependent family of sirtuins, which was previously thought to function primarily as a deacetylase has been shown to have potent desuccinylase activity [34]. In support, Sirt5-deficient mice have increased succinylation at specific lysine residues of the enzyme carbamoyl phosphate synthase 1 (CPS1), a known target of succinylation.…”

Section: Reviewmentioning

confidence: 99%

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Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

553

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

553

445

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“…Recently, the human sirtuin protein (Sirt5) was showed to be an efficient NAD ϩ -dependent protein lysine desuccinylase and demalonylase (8,71). In E. coli, a sirtuin-like protein CobB has deacetylase/desuccinylase activity (14).…”

Section: Confirmation Of Succinylated Proteins By Immunoprecipitationmentioning

confidence: 99%

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Yang

Wang

Chen

et al. 2015

Molecular & Cellular Proteomics

122

139

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Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtb remain unexplored. Here, we performed a global succinylome analysis of the virulent Mtb strain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetylCoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitro assays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen.

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“…Sirt3 influences stress responses and deacetylates many metabolic enzymes, whereas carbamoylphosphate synthetase 1 (CPS1) constitutes the only confirmed physiological Sirt5 deacetylation substrate [14][15][16] . Recently, Sirt5 was found to display stronger desuccinylase and demalonylase activity and to desuccinylate CPS1 at a Lys that can carry both succinylations and acetylations 17 . For Sirt4, no deacetylation substrate has yet been identified.…”

mentioning

confidence: 99%

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

et al. 2013

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Sirtuin enzymes regulate metabolism and aging processes through deacetylation of acetyllysines in target proteins. More than 6,800 mammalian acetylation sites are known, but few targets have been assigned to most sirtuin isoforms, hampering our understanding of sirtuin function. Here we describe a peptide microarray system displaying 6,802 human acetylation sites for the parallel characterisation of their modification by deacetylases. Deacetylation data for all seven human sirtuins obtained with this system reveal isoform-specific substrate preferences and deacetylation substrate candidates for all sirtuin isoforms, including Sirt4. We confirm malate dehydrogenase protein as a Sirt3 substrate and show that peroxiredoxin 1 and high-mobility group B1 protein are deacetylated by Sirt5 and Sirt1, respectively, at the identified sites, rendering them likely new in vivo substrates. Our microarray platform enables parallel studies on physiological acetylation sites and the deacetylation data presented provide an exciting resource for the identification of novel substrates for all human sirtuins.

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Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase

Cited by 1,239 publications

References 32 publications

Succinate: a metabolic signal in inflammation

Succinate: a metabolic signal in inflammation

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

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