Download Regulation of cellular homoeostasis by reversible lysine acetylation

© The Authors Journal compilation © 2012 Biochemical Society
Essays Biochem. (2012) 52, 13–22: doi: 10.1042/BSE0520013
2
Regulation of cellular
homoeostasis by reversible
lysine acetylation
Iain Scott1
Center for Molecular Medicine, National Heart, Lung, and Blood
Institute, National Institutes of Health, Room 5-3216, Building
10-CRC, 9000 Rockville Pike, Bethesda, MD 20892, U.S.A.
Abstract
Acetylation, through the post-transcriptional modification of histones, is a wellestablished regulator of gene transcription. More recent research has also identified an important role for acetylation in the regulation of non-histone proteins,
both inside and outside the nucleus. As a fast (and reversible) post-translational
process, acetylation allows cells to rapidly alter the function of existing proteins,
making it ideally suited to biological programmes that require an immediate
response to changing conditions. Using metabolic programmes as an example,
the present chapter looks at how reversible acetylation can be used to regulate
important enzymes in an ever-changing cellular environment.
Introduction
Organisms exist in a constant state of flux and, therefore, require the ability to
adapt to changes in their environment. At the cellular level, these environmental
changes (whether they are metabolic, nutritional, protective etc.) can generally
be dealt with by altering the amount and activity of specific regulatory proteins.
[email protected]
13
14
Essays in Biochemistry volume 52 2012
When environmental changes occur slowly, the cell can respond by producing
greater amounts of any protein it needs to maintain physiological homoeostasis.
However, when rapid changes occur that require an immediate response, the
cell cannot afford to wait for the transcription/translation machinery to meet
the demand. In these cases, cells often have the required proteins and mechanisms already in place to take care of any problems. Although it is important for
these types of proteins to exist at all times, it is equally important that the cell
can switch them on and off when required. For example, leaving many proteins
continually activated could lead to a high energetic burden for the cell, especially if the activated protein requires biochemical energy (ATP, GTP etc.) to
function. As such, many fast-acting biochemical mechanisms have evolved to
act as regulators of protein activity, and these include the PTM (post-translation
modification) of proteins.
PTMs usually involve the addition of small chemicals or proteins to enzymes,
which act to increase or diminish their activity. One of the most widely studied PTMs is lysine acetylation, which involves the addition of an acetyl group
to the ε-amino group of lysine residues by a lysine acetyltransferase. This process is reversible, and a second group of enzymes, deacetylases, can remove this
acetyl group and return the substrate protein to its former state. Acetylation,
as a PTM, was first discovered in the 1960s in studies investigating histones [1].
During gene expression or DNA replication, histones can become acetylated.
This changes the charge of the protein and reduces its affinity for DNA, allowing genes to become more accessible to polymerases [2]. More recent work has
established that lysine acetylation is not restricted to histones, and is in fact
present in a huge number of protein groups [3–6]. These acetylation/deacetylation events have been shown to be involved in many processes, regulating
mechanisms as disparate as cytoskeletal dynamics, fat metabolism and protein
localization.
Using mainly glucose homoeostatic pathways as an example, this chapter
will introduce the main mechanisms involved in regulating the acetylation status
of non-histone proteins, before focusing on how sirtuin deacetylases control
multiple aspects of mammalian metabolism.
Controlling the acetylation status of proteins in the nucleus
and cytoplasm
As stated above, lysine acetylation is a reversible PTM and is carried out
by opposing sets of enzymes called acetyltransferases (addition of an acetyl
group) and deacetylases (removal of an acetyl group) (please see Chapter 1
for a detailed review). Many acetyltransfersases and deacetylases are found in
discrete cellular locations (e.g. restricted to the nucleus); however, some have
the ability to shuttle back and forth between compartments (e.g. from the
nucleus to the cytoplasm) under different physiological conditions. The acetyl
groups added by acetyltransferases come from the coenzyme acetyl-CoA,
© The Authors Journal compilation © 2012 Biochemical Society
I. Scott
15
and are added to the ε-amino group of protein lysine residues. As such, the
acetylation status of any substrate protein is the result of a combination of
three basic factors: (i) the current activity of its specific acetyltransferase(s),
(ii) the current activity of its deacetylase(s), and (iii) the availability of acetylCoA as an acetylation substrate. Adding another layer of complexity is the
fact that proteins may contain multiple lysine residues, and the acetylation
status of different residues may be regulated by different acetyltransferases
and deacetylases. The differential acetylation of lysine residues on the same
protein may then lead to different biological outcomes (e.g. deacetylation of
one residue may activate a protein, whereas the same process at a different
residue may inactivate it). Finally, there may be cross-talk between different
types of lysine PTM (ubiquitination, SUMOylation, methylation etc.), all of
which occur at the same lysine residue ε-amino group. As such, the addition
of another type of lysine PTM may block the ability of a protein to become
acetylated, thereby attenuating regulation using this process. Clearly, the control of protein function by acetylation requires the co-ordination of multiple
cellular regulation systems.
Acetyltransferases
There are three major acetyltransferase [also known as HATs (histone acetyltransferases) or, more accurately, KATs (lysine acetyltransferases)] families,
and member proteins from each group have been implicated in the control of
cellular homoeostasis (reviewed in [7]). The GNAT [GCN5 (general control
of amino acid synthesis 5)-related N-acetyltransferase] family is very large and
contains numerous proteins, such as PCAF {p300 (E1A-associated protein of
300 kDa)/CBP [CREB (cAMP-response-element-binding protein)-binding
protein]-associated factor}, ELP3 (elongation protein 3) and GCN5, which
is the archetypal member of the group and the first KAT to have been discovered [8]. The second family, MYST acetyltransferases, contains TIP60 [Tat
(transactivator of transcription)-interactive protein 60 kDa], MOZ (monocytic leukaemic zinc-finger protein), HBO1 (histone acetyltransferase binding to Orc1), MORF (MOZ-related factor) and MOF (male absent on first).
These proteins have a wide range of acetylation substrates, and regulate pathways both in the nucleus (transcription, DNA repair etc.) and the cytoplasm
(e.g. gluconeogenesis). Finally, the third group of KATs contains two homologous members, p300 and CBP, which are well characterized as transcriptional
activators. Acetyltransferases often form large multimeric complexes with
accessory proteins which may facilitate, or be required, for their activity [9].
Searches for small molecule inhibitors of KAT function have identified several
synthetic and natural chemicals, such as curcumin and garcinol, which have
potential pharmaceutical applications [7]. Given the number of KATs characterized in the human genome (~20), and the number of known acetylated
proteins (~1750), it would appear that these enzymes have a wide substrate
specificity.
© The Authors Journal compilation © 2012 Biochemical Society
16
Essays in Biochemistry volume 52 2012
Deacetylases
Like KATs, deacetylase proteins [also known as HDACs (histone deacetylases) or KDACs (lysine deacetylases)] are grouped into families. The class I
(HDAC1–HDAC3 and HDAC8) and class IV (HDAC11) KDACs are predominantly localized in the nucleus, whereas the class II KDACs (HDAC4–
HDAC7, HDAC9 and HDAC10) can shuttle between the nucleus and the
cytoplasm [10]. Class III KDACs, which are NAD+-dependent deacetylases,
are described below. Class I, II and IV KDACs are zinc-dependent enzymes,
which have a conserved catalytic domain consisting of two histidine residues
and a zinc ion [10]. These enzymes, whose activity can be blocked using TSA
(trichostatin A), deacetylate a wide range of nuclear and cytosolic proteins
including transcription factors [such as p53 and NF-κB (nuclear factor κB)] and
cytoskeletal proteins (such as α-tubulin).
Sirtuins: deacetylases that regulate numerous
metabolic pathways
One of the most interesting groups of deacetylase enzymes, in terms of cellular
homoeostasis, is the class III KDACs, also known as the sirtuins. Mammalian
sirtuin proteins are named after Sir2 (silent information regulator 2), a gene
that was identified as controlling lifespan in yeast [11], In humans there are
seven members of the sirtuin family (SIRT1–7), and the different proteins can
be found in discrete cellular locations (e.g. SIRT1 in the nucleus and SIRT3 in
mitochondria). The majority of the proteins exhibit KDAC activity, and appear
to function in numerous cellular pathways, removing acetyl groups in order to
increase or decrease the activity of their substrates.
In terms of metabolism, sirtuin proteins are intricately linked to the energy
status of the cell through the coenzyme NAD+. NAD+ (and its reduced form
NADH) acts as an electron transfer protein in metabolic redox reactions, with
the ratio between the electron-accepting and -donating forms regulating the
activity of many enzyme pathways. Sirtuin proteins are linked to this energetic control by two complementary mechanisms. First, sirtuins are NAD+dependent enzymes, and their activity is enhanced when cellular NAD+ levels
are increased. Secondly, one of the by-products of the NAD+-dependent sirtuin deacetylation reaction is NAM (nicotinamide), which acts as an inhibitor
of sirtuins [12]. In effect, the enzymatic activity of these proteins contains an
in-built regulation system to prevent excessive deacetylation of target proteins.
This negative-feedback control remains in place until the energetic status of the
cell changes, and the renewed requirement for free NAD+ can be met, in part,
by the conversion of NAM into NAD+ through metabolic salvage pathways
(Figure 1).
The regulation of metabolism by sirtuin proteins has made them a prime
target for research into related human diseases. Several major pathological conditions (including cancer, Type 2 diabetes and neurological disorders) are caused or
© The Authors Journal compilation © 2012 Biochemical Society
I. Scott
17
Figure 1. Metabolic pathways involving acetyltransferases and deacetylases
Cellular fuel sources such as carbohydrates, fats and proteins are metabolized through different
pathways to form acetyl-CoA. This coenzyme can enter the TCA (tricarboxylic acid) cycle to
drive oxidative metabolism, leading to the formation of reduced NAD (in the form of NADH),
or it can be used as a substrate for acetylation of proteins by acetyltransferases (KATs). The
NAD+ from metabolic redox reactions can activate sirtuin deacetylases (SIRT KDACs), which
remove the acetyl groups from substrate proteins acetylated by KATs. One of the by-products
of the deacetylation reaction is NAM, which acts as a negative-feedback regulator, reducing
SIRT KDAC activity. NAM can then be returned to the NAD pool as required through the NAD
salvage pathway.
characterized by defects in metabolic control (reviewed in [13]). The ability of
sirtuin proteins (particularly SIRT1 and SIRT3) to mediate mitochondrial biology and bioenergetics is especially important. Mitochondria are the primary site
of damaging ROS (reactive oxygen species) production, and the deacetylation
function of sirtuin proteins is crucial in the regulation of antioxidant genes which
ameliorate ROS damage [14]. ROS damage has been linked to loss of mitochondrial function, which is a major factor in the development of metabolic diseases
(such as diabetes) and aging-related pathologies (such as Alzheimer’s disease
and Parkinson’s disease) [13]. The role of sirtuin proteins in human disease is
currently expanding rapidly, and will no doubt be an area of great importance for
some time to come.
Although our understanding of the regulation of sirtuin enzyme activity
has greatly increased, it is the downstream effects of sirtuin function that have
received the most focus. Therefore the role of three major sirtuin deacetylase
proteins, SIRT1, SIRT2 and SIRT6, in the regulation of several cellular homoeostatic pathways is discussed below.
SIRT1
SIRT1 is the archetypal member of the mammalian sirtuin family and is the
major nuclear deacetylase in this group. One major area of SIRT1 research has
been its role in CR (caloric restriction), which has long been known to increase
lifespan in a variety of organisms. CR was first shown to have an effect on sirtuin
© The Authors Journal compilation © 2012 Biochemical Society
18
Essays in Biochemistry volume 52 2012
activity in yeast, where the reduction in calories caused an increase in available NAD+, which is required for sirtuin function [11]. The ability of SIRT1
homologues to increase lifespan in various organisms led to the search for novel
chemical activators. One of the best known is resveratrol, an antioxidant found
in red wine. Resveratrol improves the enzyme activity of SIRT1 by increasing
its ability to bind and deacetylate substrates [15].
Given the NAD+ requirement in sirtuin function, systems which regulate
the intracellular NAD+/NADH ratio have a powerful role in regulating SIRT1.
AMPK (AMP-activated protein kinase), a key energy homoeostasis enzyme,
helps to regulate this balance. One of the first studies to link AMPK function
and SIRT1 activity looked at glucose metabolism. This found that reduced levels of glucose led to the activation of AMPK, which induced the NAD+ salvage pathway to create more NAD+, which activated SIRT1 [16]. These results
were further extended by studies demonstrating that AMPK, acting as a cellular
fuel sensor, could increase the transcriptional activity of proteins regulated by
SIRT1 [17]. The depletion of cellular energy leads to the activation of AMPK,
which stimulates SIRT1 in the manner described above. SIRT1 then deacetylates, and activates, several transcription regulators, such as FOXO (forkhead
box O) proteins and PGC-1α (peroxisome-proliferator-activated receptor γ coactivator 1α) [18].
PGC-1α is a major transcriptional co-activator, and is involved in cellular
metabolism and mitochondrial biogenesis (the formation of new mitochondria). It has been demonstrated that, in the liver, SIRT1 is activated in response
to fasting, which leads to the deacetylation of PGC-1α [19]. Deacetylated
PGC-1α can then bind to the promoter regions of fasting-response genes and
regulate how they function. In this case, the lowered availability of nutrients in
the cell led to PGC-1α switching on genes that produce more glucose (through
gluconeogenesis; see below) and switching off genes that consume glucose,
such as those involved in glycolysis [19]. When nutrient conditions return to
normal, acetylation is again used to modulate PGC-1α function. To counter the
activity of SIRT1, a nuclear-localized KAT called GCN5 acetylates PGC-1α at
specific residues. This causes the transcriptional co-activator to detach from the
promoter regions of its target genes and form non-functional foci in the nucleus
[20]. To summarize, reversible acetylation, involving counteracting KATs and
KDACs, is central to the transcriptional control of glucose homoeostasis.
SIRT2
SIRT2 is a unique member of the sirtuin family, in that many of its functions
occur in the cytoplasm. Although much less studied than SIRT1, it is becoming increasingly apparent that SIRT2 is involved in the regulation of numerous pathways. Much of the early research into SIRT2 focused on its role in
controlling aspects of cellular architecture, particularly the cytoskeleton.
SIRT2 was shown to interact with, and deacetylate, tubulin, a key protein in
© The Authors Journal compilation © 2012 Biochemical Society
I. Scott
19
microtubules. Changes in the acetylation status of tubulin has an impact on the
stability of microtubules, and therefore the deacetylation of tubulin by SIRT2
may be involved in regulating changes to cytoskeletal architecture (reviewed in
[21]). These changes also linked SIRT2 to the cell cycle, as major changes in the
cytoskeleton are required during mitosis. It has been shown that an increase in
SIRT2 protein levels occurs at the G2/M transition of the cell cycle, and that
cells overexpressing a deacetylase-null mutant copy of SIRT2 were slowed at
this stage [22].
More recent research has shown that SIRT2, and the opposing KAT p300,
regulate a major energetic homoeostatic mechanism. When organisms face lownutrient conditions (e.g. fasting, scarcity of food/prey etc.), several metabolic
pathways can be activated which increase the availability of nutrients to cells.
To prevent hypoglycaemia, mammals can activate two main pathways that lead
to increased cellular glucose concentrations: glycogenolysis (the breakdown of
stored glycogen) or gluconeogenesis (the de novo formation of glucose from
non-carbohydrate sources such as lactate or amino acids). The first irreversible rate-limiting step of gluconeogenesis is the conversion of oxaloacetate into
phosphoenolpyruvate, which is carried out by the enzyme PEPCK1 (phosphoenolpyruvate carboxykinase). A proteomics screen of metabolic pathways in
2010 identified this enzyme as an acetylation substrate [6], indicating that the
process may be regulated by this PTM. Although this turned out to be true, this
regulation was not as simple as perhaps first imagined.
PEPCK1 is activated under low-glucose conditions, which drives gluconeogenesis in the liver (and to a lesser extent, the kidneys), leading to an increase
in available glucose. At the least-complex level, the acetylation of PEPCK1
would theoretically act as a molecular switch, with the addition of an acetyl
group switching the protein on or off (with deacetylation acting in the opposite
direction). However, the regulation of PEPCK1 has evolved in a more complex manner, and involves the interaction of two lysine PTMs. When glucose
levels are low, SIRT2 is transcriptionally activated, leading to increased protein
abundance and deacetylation activity. SIRT2 then deacetylates PEPCK1, which
leads to a stabilization of this protein and an increase in gluconeogenesis [23].
Under the opposite nutrient conditions the levels of SIRT2 are diminished and
the abundance and activity of the counteracting KAT (p300) are increased. p300
acetylates PEPCK1 under these high-glucose conditions, which, using our simple theory, would be enough to block PEPCK1 function. However, this regulation goes a step further, as the acetylation of PEPCK1 by p300 causes it to be
removed altogether. When PEPCK1 is acetylated, it marks it for ubiquitination by the Ub (ubiquitin) E3 ligase UBR5. This ubiquitinated PEPCK1 is then
targeted for degradation by the proteasome, completely inhibiting gluconeogenetic activity [23]. Therefore reversible acetylation (by p300 and SIRT2) not
only regulates this major pathway, it provides a mechanism for two very different lysine PTMs to work together.
© The Authors Journal compilation © 2012 Biochemical Society
20
Essays in Biochemistry volume 52 2012
SIRT6
SIRT6 is a nuclear-localized deacetylase, which controls many pathways by regulating (or co-regulating) processes related to transcription and DNA interactions. SIRT6 is thought to display a weaker deacetylase activity (approximately
1000-fold less) than some other sirtuins, but can still catalyse the reaction as
required [24]. So far the majority of research on SIRT6 has focused on its true
HDAC activity, and it has been shown to remove the acetyl groups from lysine
residues of histone H3 at Lys9 (H3K9) and Lys56 (H3K56) (reviewed in [25]).
This function has linked SIRT6 to DNA repair [for example at DSBs (doublestrand breaks) caused by oxidative damage] and the maintenance of telomeres
[25]. With regard to cellular homoeostasis, SIRT6 has been found to have an
important role in the transcriptional response to changes in glucose metabolism.
Many alterations in cellular homoeostasis are regulated at the transcriptional
level, and one of the main transcription factors involved is HIF1α (hypoxiainducible factor 1α). This protein, originally identified as a factor mediating
responses to cellular hypoxia, has been implicated in several other capacities.
To be activated, HIF1α is acetylated by the KAT p300, and this leads to the
initiation of target gene transcription (reviewed in [26]). Under normal glucose concentrations, SIRT6 interacts with HIF1α and deacetylates it, preventing the transcription factor from activating genes. This allows normal cellular
energetic pathways (such as increased mitochondrial oxidative phosphorylation
and decreased glycolysis) to take place [27]. However, when the energy balance
of the cell shifts to low-glucose conditions, SIRT6 is inactivated and HIF1α
becomes acetylated (most probably by p300) and its transcriptional activity is
enhanced [27]. Further research has shown that SIRT6 directly binds to, and
deacetylates, the promoter regions of several major glycolytic genes (such as
lactate dehydrogenase and pyruvate dehydrogenase kinase 1), indicating that
SIRT6 may be a master regulator of cellular glucose metabolism at the transcriptional level [26].
Conclusions
Despite being a relatively young field of research, our knowledge of how proteins are regulated by lysine acetylation has grown at a prodigious rate. In the
space of approximately 15 years, we have identified suites of acetyltransferases
and deacetylases, established their enzymatic functions and catalogued some of
their substrates; however, it is clear from recent proteomic studies that we have
so far only scratched the surface of acetylation. Hundreds (if not thousands) of
proteins in every compartment of the cell have now been identified as lysine
acetylation substrates, and there is much still to discover about what all of these
modifications mean in terms of cellular function. For each acetylated protein, we
have several questions to ask. What enzyme adds or removes the acetyl group?
How is it regulated? How does it change the function of the protein? How does
acetylation interact with other lysine PTMs?
© The Authors Journal compilation © 2012 Biochemical Society
I. Scott
21
When it comes to cellular metabolism and physiology, lysine acetylation
takes on an even deeper significance. The base unit of acetylation, the acetyl
group of acetyl-CoA, is a breakdown product of fuel metabolism. The sirtuins,
one of the most metabolically relevant deacetylase groups, are driven by fundamental biochemical reactions that are closely linked to cellular energetic states.
Almost every metabolic pathway studied contains enzymes that are modified,
and perhaps regulated, by acetylation. It is clear, therefore, that acetylation
and metabolism are intricately linked. As such, future work will be required
to delineate how much feedback regulation there is between global cellular
homoeostasis and global protein acetylation.
Summary
•
•
•
•
Lysine acetylation is a wide-spread, rapid and reversible PTM.
The counteracting activity of acetyltransferases and deacetylases regulates the acetylation status, and thus activity, of a vast number of proteins.
Cellular programmes that need to react quickly to changing conditions,
such as metabolic pathways, are prime targets of regulation by lysine
acetylation.
The sirtuin family of lysine deacetylases both regulate and are regulated
by cellular metabolic and physiological conditions.
The work of the author is supported by the intramural research programme of the
National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health.
The author is deeply indebted to his mentor, Michael Sack, and wishes to thank him
for his help and support.
References
1.
2.
3.
4.
5.
6.
7.
Pogo, B.G., Allfrey, V.G. and Mirsky, A.E. (1966) RNA synthesis and histone acetylation during the
course of gene activation in lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 55, 805–812
Winter, S. and Fischle, W. (2010) Epigenetic markers and their cross-talk. Essays Biochem. 48,
45–61
Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L. et al.
(2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.
Mol. Cell 23, 607–618
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C., Olsen, J.V. and
Mann, M. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular
functions. Science 325, 834–840
Wang, Q., Zhang, Y., Yang, C., Xiong, H., Lin, Y., Yao, J., Li, H., Xie, L., Zhao, W., Yao, Y., et al.
(2010) Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic
flux. Science 327, 1004–1007
Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., Yao, J., Zhou, L., Zeng, Y., Li, H. et al.
(2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004
Selvi, R.B. and Kundu, T.K. (2009) Reversible acetylation of chromatin: implication in regulation of
gene expression, disease and therapeutics. Biotechnol. J. 4, 375–390
© The Authors Journal compilation © 2012 Biochemical Society
22
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Essays in Biochemistry volume 52 2012
Brownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y. and Allis, C.D.
(1996) Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone
acetylation to gene activation. Cell 84, 843–851
Grant, P.A., Eberharter, A., John, S., Cook, R.G., Turner, B.M. and Workman, J.L. (1999).
Expanded lysine acetylation specificity of Gcn5 in native complexes. J. Biol. Chem. 274,
5895–5900
Riccio, A. (2010) New endogenous regulators of class I histone deacetylases. Sci. Signal. 3, pe1
Lin, S.J., Defossez, P.A. and Guarente, L. (2000) Requirement of NAD and SIR2 for life-span
extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128
Bitterman, K.J., Anderson, R.M., Cohen, H.Y., Latorre-Esteves, M. and Sinclair, D.A. (2002)
Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast
sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107
Chalkiadaki, A. and Guarente, L. (2012) Sirtuins mediate mammalian metabolic responses to
nutrient availability. Nat. Rev. Endocrinol., doi:10.1038/nrendo.2011.225
Webster, B.R., Lu, Z., Sack, M.N. and Scott, I. (2012) The role of sirtuins in modulating redox
stressors. Free Radical Biol. Med. 52, 281–290
Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G., Zipkin, R.E.,
Chung, P., Kisielewski, A., Zhang, L.L. et al. (2003) Small molecule activators of sirtuins extend
Saccharomyces cerevisiae lifespan. Nature 425, 191–196
Fulco, M., Cen, Y., Zhao, P., Hoffman, E.P., McBurney, M.W., Sauve, A.A. and Sartorelli, V. (2008)
Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through
AMPK-mediated regulation of Nampt. Dev. Cell 14, 661–673
Canto, C., Gerhart-Hines, Z., Feige, J.N., Lagouge, M., Noriega, L., Milne, J.C., Elliott, P.J.,
Puigserver, P. and Auwerx, J. (2009) AMPK regulates energy expenditure by modulating NAD+
metabolism and SIRT1 activity. Nature 458, 1056–1060
Canto, C. and Auwerx, J. (2009) PGC-1α, SIRT1 and AMPK, an energy sensing network that
controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105
Rodgers, J.T., Lerin, C., Haas, W., Gygi, S.P., Spiegelman, B.M. and Puigserver, P. (2005) Nutrient
control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118
Lerin, C., Rodgers, J.T., Kalume, D.E., Kim, S.H., Pandey, A. and Puigserver, P. (2006). GCN5
acetyltransferase complex controls glucose metabolism through transcriptional repression of
PGC-1α. Cell Metab. 3, 429–438
Inoue, T., Hiratsuka, M., Osaki, M. and Oshimura, M. (2007) The molecular biology of mammalian
SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle 2, 1011–1018
Dryden, S.C., Nahhas, F.A., Nowak, J.E., Goustin, A.S. and Tainsky, M.A. (2003) Role for human
SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell.
Biol. 23, 3173–3185
Jiang, W., Wang, S., Xiao, M., Lin, Y., Zhou, L., Lei, Q., Xiong, Y., Guan, K.L. and Zhao, S. (2011)
Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5
ubiquitin ligase. Mol. Cell 43, 33–44
Pan, P.W., Feldman, J.L., Devries, M.K., Dong, A., Edwards, A.M. and Denu, J.M. (2006) Structure
and biochemical functions of SIRT6. J. Biol. Chem. 286, 14575–14587
Tennen, R.I. and Chua, K.F. (2011) Chromatin regulation and genome maintenance by mammalian
SIRT6. Trends Biochem. Sci. 36, 39–46
Zhong, L. and Mostoslavsky, R. (2011) SIRT6: a master epigenetic gatekeeper of glucose
metabolism. Transcription 1, 17–21
Zhong, L., D’Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A.,
Marinelli, B., Wikstrom, J.D., Nir, T. et al. (2010) The histone deacetylase Sirt6 regulates glucose
homeostasis via Hif1α. Cell 140, 280–293
© The Authors Journal compilation © 2012 Biochemical Society