Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101725


Historical Background

Sirtuins are a conserved family of proteins with homology to silent information regulator 2 (Sir2) of Saccharomyces cerevisiae, initially identified as genetic silencing factors (Rine et al. 1979) and later found to extend longevity in yeast, worms, and flies. Subsequent studies showed that Sir2 is a NAD+-dependent deacetylase that targets both histones and nonhistone proteins (Imai et al. 2000) and it also possesses mono-ADP-ribosyltransferase activity, functions that are highly conserved during evolution. Importantly, NAD+-dependent deacetylation by Sir2 was later linked to lifespan extension associated with calorie restriction (Lin et al. 2000). Mammals have seven homologs of Sir2 (SIRT1–SIRT7), of which SIRT1 is the closest mammalian homolog in structure and function to yeast Sir2. All sirtuins share a conserved NAD+-binding site and a catalytic core domain of ∼275 amino acids that is flanked by N- and C-terminal extensions. The extensions are heterogeneous in terms of length and sequence, and they have been reported to play various roles, such as ensuring a proper subcellular localization, regulating the oligomerization state, and exerting autoregulation mechanisms. Phylogenetic analyses revealed that the conserved sirtuin core domain sequences of eukaryotic organisms are categorized into four different classes: SIRT1–SIRT3 belong to class I, SIRT4 to class II, SIRT5 to class III, and SIRT6 and SIRT7 to class IV. The seven sirtuins, however, differ in terms of subcellular localization, enzymatic activity, and targets (Table 1). Because the enzymatic reaction catalyzed by sirtuins requires NAD+ as a substrate, the concentration of which is determined by the energy state of the cell, the expression and activity of these enzymes are tightly coupled to changes in cellular energy/redox status. Sirtuins have been suggested to play a crucial role in mounting physiological adaptive responses to changes in environmental conditions. As such, sirtuins are considered to be metabolic and stress sensor proteins. It is important to note that the activity of sirtuins can also be influenced by other modifications such as by their physical interaction with other proteins and/or following their own posttranslational modification(s). As a result of their status as metabolic sensors and also because they target multiple proteins involved in regulation of many diverse processes, ranging from cell cycle progression and mitochondrial function to metabolism and energy homeostasis, interest in this class of proteins has increased dramatically over the past decade.
SIRT2, Table 1

Sirtuin subcellular localization, enzymatic activity, and major targets



Subcellular localization

Enzymatic activity

Representative targets



Nucleus, cytosol


p53, FOXO, PGC-1α, PPARγ, NF-κB, H3K9



Cytosol, nucleus

Deacetylation, demyristoylation

α-tubulin, FOXO, H4K16, NF-κB, PEPCK, ACLY














Deacetylation, demalonylation, desuccinylation





Deacetylation, ADP-ribosylation

H3K9, HIF-1α, PARP1, NF-κB





Pol I, H3K18

AceCS2 acetyl-CoA synthetase 2, ACLY ATP citrate lyase, CPS1 carbamoyl-phosphate synthase 1, FOX forkhead box, GDH glutamate dehydrogenase, H3K histone H3 Lys, H4K16 histone H4 Lys16, HIF hypoxia-inducible factor, IDH2 isocitrate dehydrogenase 2, MCD malonyl-CoA decarboxylase, NF-κB nuclear factor-κB, PARP1 poly-ADP-ribose polymerase 1, PEPCK1 phosphoenolpyruvate carboxykinase 1, PGC1α PPARγ co-activator 1α, Pol I polymerase I, PPAR peroxisome proliferator-activated receptor, SOD superoxide dismutase

Biological Properties of SIRT2

Several SIRT2 transcript variants result from alternative splicing of this gene. However, only two variants have confirmed protein products of physiological relevance. The longer, full-length SIRT2 variant 1 encodes a 389-amino acid protein with a predicted molecular weight of 43.2 kDa, whereas variant 2, which is lacking the first 37 N-terminal amino acids, encodes a 352-amino acid protein with a predicted molecular weight of 39.5 kDa. A leucine-rich nuclear export signal (NES) has been identified within the N-terminal region of these two isoforms (Fig. 1). Since deletion of the NES from these SIRT2 isoforms led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.
SIRT2, Fig. 1

Schematic representation of human SIRT2 protein. The blue box depicts the SIRT2 catalytic core domain, which is flanked by N- and C-terminal extensions (gray boxes). The numbers below indicate amino acid numbers for orientation. Two isoforms (IF1 and IF2) are shown for SIRT2. Phosphorylation sites (P) and the nuclear export sequence (NES) are indicated

To understand the detailed mechanism of sirtuin activity, several laboratories have attempted to determine the crystal structure of sirtuin family members. The first crystal structure of a mammalian sirtuin described was that of SIRT2 (Finnin et al. 2001). Subsequently, other structures have been solved, and currently there are more than 40 described, alone or in complex with various ligands. The crystal structure of the catalytic core of human SIRT2 reveals an NAD+-binding domain, which is a variant of the Rossmann fold, and a smaller domain composed of a helical module and a zinc-binding module. A conserved large groove at the interface of the two domains is the likely site of catalysis based on mutagenesis. Intersecting this large groove, there is a pocket formed by the helical module (Fig. 2).
SIRT2, Fig. 2

The crystal structure of human SIRT2. Two different views of the overall structure of the SIRT2 catalytic core rotated by 90°. The NAD+-binding domain consists of a variant of the Rossmann fold (right, in blue), whereas the smaller domain is made up of two modules. One module (gray) binds a zinc atom (magenta), and the other contains a hydrophobic pocket (red) (Figure adapted from Finnin et al. 2001)

The seven mammalian sirtuins occupy discrete subcellular compartments (Table 1). SIRT2 is the only primarily cytoplasmic isoform that colocalizes, at least in part, with the microtubule network (North et al. 2003). Moreover, SIRT2 can also shuttle to the nucleus during the G2/M phase transition of the cell cycle (Vaquero et al. 2006), suggesting that the deacetylase activity of SIRT2 is not restricted to cytosolic proteins. It is currently unclear how SIRT2 translocates into the nucleus because the protein lacks any obvious nuclear localization signal (NLS). Interestingly, it has been recently shown that SIRT2 is also expressed in mitochondria, where it modulates mitochondrial metabolism.

Similar to other sirtuin isoforms, SIRT2 also displays ubiquitous distribution. SIRT2 is expressed in a wide variety of tissues and organs and has been detected mainly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, in particular in the cortex, striatum, hippocampus, and spinal cord. Particularly high SIRT2 protein expression in the brain is found in myelin-producing oligodendrocytes, correlating with the expression profiles of the differentiation markers CNPase (2′,3′-cyclic nucleotide 3-phosphodiesterase) and MBP (myelin basic protein) (Li et al. 2007). It has also been reported that SIRT2 mRNA is the most prominently expressed sirtuin family member in both adipose tissue and in cultured adipocytes.

SIRT2 has traditionally been considered a robust deacetylase, and its known biological functions are attributed to this enzymatic activity. Indeed, SIRT2 was originally identified as an α-tubulin deacetylase on lysine-40, both in vitro and in vivo (North et al. 2003). Subsequently, many diverse SIRT2 protein substrates have been identified. Recently, SIRT2 has been found to also remove long chain fatty acyl groups, such as myristoyl, from lysine residues, with a catalytic efficiency comparable to that of removing an acetyl group (Teng et al. 2015). However, it remains unclear whether the demyristoylase activity of SIRT2 has any physiological relevance and whether it contributes to its reported biological roles.

Regulation of SIRT2 Expression and Activity by Energy Availability, PTMs, and Transcriptional Mechanisms

Multiple lines of evidence indicate that SIRT2 expression is modulated in response to energy availability, resulting in induction during low energy status and repression during states of energy excess. Supporting the link between calorie restriction and SIRT2, mice subjected to long-term calorie restriction exhibited an increase in SIRT2 protein levels in the white adipose tissue (WAT) and kidney but not in the liver or brain (Fei Wang et al. 2007). Moreover, fasting induces SIRT2 mRNA and protein expression in WAT (Wang and Tong 2009). In a human study, SIRT2 gene expression levels increased in peripheral blood mononuclear cells of overweight subjects following an 8-week low-calorie diet. In contrast, SIRT2 protein expression in visceral WAT from human obese subjects and high-fat diet (HFD)-fed mice was downregulated compared with lean controls (Krishnan et al. 2012). SIRT2 levels can also change in response to environmental temperature, as cold exposure has been shown to induce SIRT2 expression in mouse brown adipose tissue (Wang and Tong 2009). Altogether, these results implicate SIRT2 in adaptive responses to environmental and diet-induced metabolic stress in various tissues.

Available data suggest a complex array of posttranslational modifications (PTMs) regulating SIRT2. To date two phosphorylation sites have been identified in SIRT2 (Fig. 1). They are located in the C-terminal extension in close proximity to each other at Ser331 and Ser335. Cyclins E-Cdk2, A-Cdk2, and p35-Cdk5 were shown to reduce SIRT2 enzymatic activity by phosphorylating residue Ser331, as measured by deacetylation of core histones and of α-tubulin (Pandithage et al. 2008). In contrast, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) enhanced SIRT2 deacetylase activity, although it is unclear which residues were phosphorylated. Moreover, overexpression of mitogen-activated protein kinase (MEK1/2), an upstream kinase of ERK1/2, led to stabilization of SIRT2. Additionally, SIRT2 is acetylated by the lysine acetyltransferase p300. Although the site of this modification has not been mapped, it interferes with the catalytic activity of SIRT2 (Han et al. 2008). Predictions of acetylation sites indicate that the C-terminal extension provides multiple target lysine residues, further supporting the concept that the N- and C-terminal regions are particularly relevant to control catalytic activities of sirtuins.

Only a few studies have explored the transcriptional regulation of SIRT2. It has been recently shown that the NK2 homeobox 2 transcription factor (Nkx2-2) binds to the SIRT2 promoter in a rat glial cell line and attenuates its expression via HDAC1. SIRT2 is also regulated by microRNAs (miRNAs). Overexpression of miR-339 in human neuroblastoma and rat pheochromocytoma cell lines attenuated SIRT2 translation. Conversely, treatment with a miR-339 inhibitor or miR-339 knockout promoted SIRT2 expression and reduced the acetylation status of its substrates NF-κB and FOXO1. In summary, the mechanisms regulating SIRT2 function and expression are only beginning to emerge. Nevertheless, the already available data suggest complex, multilevel control comparable with the more extensively studied members of the sirtuin family.

Most Relevant SIRT2 Actions

Molecular studies revealed that SIRT2 is involved in the regulation of diverse cellular processes ranging from cell cycle regulation, cancer progression, neurodegeneration, to lipid and glucose metabolism (Fig. 3).
SIRT2, Fig. 3

An overview of the cellular processes regulated by SIRT2. Below each process is represented the substrate(s) responsible for the observed effect

The subcellular localization and target substrates of SIRT2 are intimately linked to cell cycle oscillations. For most of the cell cycle, SIRT2 is located in the cytosol, where it targets and deacetylates α-tubulin at lysine-40, a modification that presumably attenuates microtubule stability (North et al. 2003). However, it is still unclear whether SIRT2 deacetylates soluble or polymerized α-tubulin. During G2/M transition and mitosis, SIRT2 transiently shuttles to the nucleus and associates with chromatin and deacetylates the histone H4 lysine 16 (H4K16) (Vaquero et al. 2006), thereby regulating chromosomal condensation during mitosis. SIRT1 also deacetylates H4K16, providing an example of potential synergistic relationship or functional redundancy between these sirtuin isoforms. Surprisingly, a similar phenomenon was observed after infection with Listeria monocytogenes, where SIRT2 deacetylated H3K18 and modified the gene transcription pattern. During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division. The mitotic checkpoint kinase BubR1 was recently described as a deacetylation target of SIRT2, and, more importantly, overexpression of SIRT2 in hypomorphic BubR1 mice extends lifespan (North et al. 2014), thus establishing a compelling connection between SIRT2 and aging. Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.

There is evidence suggesting both tumor suppressor and oncogenic roles of sirtuins. Genetic studies proposed a tumor suppressor role for SIRT2 by preventing chromosomal instability during mitosis. Remarkably, aged SIRT2 knockout (KO) mice show increased tumor incidence compared with wild-type (WT) controls (Kim et al. 2011). It has also been reported that SIRT2 expression is decreased in human glioma tissues and cell lines, and ectopic expression of SIRT2 in glioma cells led to a remarkable reduction of cell proliferation and colony formation capacity, through the deacetylation of the p65 subunit of NF-κB. In contrast, SIRT2 was also shown to adopt a contrary role by promoting tumorigenesis, based on the observation that SIRT2 deacetylates and inhibits the activity of p53 and this might result in a tumor-permissive phenotype. SIRT2 mRNA is elevated in CD34+ cells isolated from patients suffering from acute myeloid leukemia. Correspondingly, small molecule inhibitors of SIRT2 have also been reported to have anticancer effects. Further studies will be required to resolve these conflicting findings and determine the therapeutic potential of targeting SIRT2 in cancer.

The high expression and temporal regulation of SIRT2 in neural tissue suggest that it is involved in the nervous system development and maintenance. SIRT2 expression in rat cerebrum and spinal cord starts to increase after birth, reaching adult levels after 21 days. Similarly, expression in the mouse cortex cannot be detected until postnatal day 17, but then persists to adulthood. Interestingly, SIRT2 appears to increase in the CNS with aging (Maxwell et al. 2011). In line with these observations, SIRT2 was characterized as a specific oligodendroglial protein, which decelerates cellular differentiation by deacetylating α-tubulin (Li et al. 2007). In contrast, another study has reported opposite effects, showing that SIRT2 knockdown delays differentiation of the rat glial cell line CG4. Given these conflicting results, the exact role of SIRT2 in neuronal development is yet to be fully established.

Several studies in cell and invertebrate models of Parkinson’s disease (PD) and Huntington’s disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members. SIRT2 positively regulates the transcription factor sterol regulatory element-binding protein 2 (SREBP-2), thereby promoting cholesterol biosynthesis in neurons (Luthi-Carter et al. 2010). Although cholesterol influences membrane thickness and fluidity and is essential for myelin membrane growth, cholesterol is also reported to have a detrimental effect in neurons and presents a risk factor in neurodegenerative diseases. Consistent with these findings, SIRT2 inhibition reduces toxicity of mutant huntingtin by decreasing sterol biosynthesis (Luthi-Carter et al. 2010). Similarly, pharmacological or genetic inhibition of SIRT2 decreases α-synuclein toxicity, a protein frequently mutated in and associated with PD (Outeiro et al. 2007). Furthermore, a recent report has shown behavioral and neuropathological phenotypic improvement in HD mouse models by a brain-permeable SIRT2 inhibitor (Chopra et al. 2012). Surprisingly, SIRT2 deficiency had no effect on disease progression in a model of HD, raising the question of whether SIRT2 inhibition affords neuronal protection in mammals generally or only under specific circumstances.

Similar to several other sirtuins, SIRT2 has been implicated in various metabolic processes including adipocyte differentiation, hepatic gluconeogenesis, and insulin action as well as the regulation of inflammatory pathways, suggesting that SIRT2 activity may ensure the coordinated regulation of several distinct metabolic functions. SIRT2 is capable to deacetylate glucokinase (GK) and phosphoenolpyruvate carboxykinase 1 (PEPCK1) (Jiang et al. 2011), destabilizing the former but stabilizing the latter. GK facilitates glucose phosphorylation, the first step leading to glycolysis and glycogenesis, and PEPCK1 is a rate-limiting enzyme of gluconeogenesis. Therefore, SIRT2 activity seems to increase hepatic glucose production that would be beneficial for glucose homeostasis in conditions of energy limitation. Interestingly, glucose itself seems to regulate SIRT2, as supplementing starved HEK293T cells with glucose resulted in a more than twofold reduction in SIRT2 mRNA. There is also evidence that SIRT2 modulates insulin sensitivity, but data have been seemingly conflicting. Recent studies showed that SIRT2 is the primary interactor and regulator of Akt activation in insulin-responsive cells under standard nutrient conditions. While SIRT2 overexpression in 3T3-L1 preadipocytes and HeLa cells enhanced insulin-induced Akt activation and phosphorylation of its downstream targets GSK3β and p70S6 kinase, pharmacological or genetic SIRT2 inhibition causes the opposite effect. In stark contrast, increased SIRT2 expression has been reported in insulin-resistant C2C12 skeletal muscle cells, and SIRT2 inhibition increased insulin-stimulated glucose uptake and improved phosphorylation of Akt and GSK3β. In white adipose tissue (WAT), SIRT2 promotes fatty acid oxidation by deacetylating and thus enhancing PGC-1α activity. Correspondingly, SIRT2 suppresses adipogenesis and promotes lipolysis in mature adipocytes by deacetylating FOXO1 (Enxuan Jing et al. 2007, Wang and Tong 2009). This process is disrupted in obese individuals, because nutrient overload induces HIF-1α, which in turn represses SIRT2 expression (Krishnan et al. 2012). Thus, it can be speculated that modulating SIRT2 activity may ameliorate, at least in part, the metabolic disturbances in the obese resulting from increased fat mass.

Pharmacological Modulation of SIRT2

Sirtuins are considered attractive therapeutic targets for metabolic and aging-related diseases, which has stimulated extensive efforts for development of sirtuin-modulating compounds. Sirtuins are also special targets because they are amenable to stimulation, besides inhibition, through small molecules. To date, several SIRT2 inhibitors have been described as having beneficial effects against neurodegeneration and cancer. A potent and selective inhibitor of SIRT2 is AGK2 with IC50 of 3.5 μM. It was demonstrated that the inhibition of SIRT2 protects against dopaminergic cell death in a Drosophila model of Parkinson’s disease (Outeiro et al. 2007). This compound has also been shown to induce caspase-3-dependent apoptosis and necrosis of C6 glioma cells. More recently, two independent studies have reported novel SIRT2 inhibitors with improved potency and selectivity. One such inhibitor, termed SirReal2, was based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. SirReal2 leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with SIRT2 inhibition in vivo. Another group developed a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with broad anticancer activity but little effect on noncancerous cells. The anticancer effect of TM correlates with its ability to decrease c-Myc levels by ubiquitination and degradation. Although no specific SIRT2 activator is currently available, the data generated thus far strongly suggest that increasing SIRT2 expression and/or activity is likely to result in improved metabolic function under conditions of dietary or genetic overnutrition. Because SIRT2 expression is downregulated in obesity and increased expression of SIRT2 augments insulin sensitivity, stimulates fatty acid oxidation, and reduces inflammation, strategies to activate SIRT2 would, in theory, allow simultaneous targeting of multiple features of metabolic disorders.


SIRT2 is a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a conserved catalytic domain, which binds NAD+. Several transcript variants result from alternative splicing of this gene. Control of SIRT2 expression involves all the major points of regulation, including transcriptional and posttranslational mechanisms, as well as microRNAs and nutrient availability. Although available data are still scarce, it can be predicted that the network of SIRT2 PTMs is as sophisticated as that of the most extensively characterized SIRT1 system. SIRT2 displays a robust deacetylase activity, although it has been suggested to perform other lysine modifications, such as demyristoylation. Despite being primarily cytosolic, SIRT2 may also shuttle to the nucleus during the G2/M transition of the cell cycle, enabling the deacetylation of both cytosolic and nuclear proteins. The currently known SIRT2 substrates/binding partners suggest a complex and apparently diverse function for this sirtuin in the cell. In line with this notion, the human SIRT2 isoform has been implicated in the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of SIRT2 activity a promising strategy for therapeutic intervention in several age-related diseases, including cancer, neurodegenerative diseases, and metabolic disorders.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.CNC-Center for Neuroscience and Cell Biology, University of CoimbraCoimbraPortugal