Sirtuins in mammals: insights into their biological function

Abstract

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

Figure 1. Sirtuin enzymatic activities

Sirtuins are NAD⁺-dependent deacetylases and mono-ADP-ribosyl transferases that regulate a wide array of proteins involved in metabolism and cell survival. The ε-acetyl lysine residues of the target protein serve as substrates for sirtuin deacetylation, which generate 2′-OAADPr as a by-product. NAM, nicotinamide.

Figure 2. Mammalian sirtuins

Mammals have seven sirtuins, SIRT1–7. All have an NAD⁺-dependent catalytic core domain that may act preferentially as a mono-ADP-ribosyl transferase (ART) and/or NAD⁺-dependent deacetylase (DAC). Additional N-terminal and/or C-terminal sequences of variable length may flank this core domain. The seven sirtuins show different cellular localization. Reprinted from Biochemical and Biophysical Research Communications, 273, Frye, R.A., Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins, 793–798, © 2000, with permission from Elsevier.

Figure 3. Classification of mammalian sirtuins

The seven mammalian sirtuins are classified into four classes according to molecular phylogenetic analysis [33]. Sirtuins from Class II, Class III and Class U (undetermined) seem to have evolved earlier than the other classes. Thus, SIRT4 and SIRT5 may be the most ancient mammalian sirtuins. Class I and Class IV sirtuins, which group SIRT2 and SIRT3 and SIRT6 and SIRT7 respectively, are only present in eukaryotes. C. alb, Candida albicans; C. ele, Caenorhabditis elegans, D.mel, Drosophila melanogaster; P. fal, Plasmodium falciparum; T. mar, Termatoga maritime.

Figure 4. Cellular functions of mammalian sirtuins

Sirtuins regulate a variety of process in mammalian cells. For example, in the nucleus, SIRT1 modulates chromatin structure by deacetylating specific lysine residues in histones H1, H3 and H4. Also, SIRT1 alters gene expression by targeting Lys¹⁰²⁰ and Lys¹⁰²⁴ of p300. Deacetylation of Tat by SIRT1 promotes HIV-1 replication. SIRT1 complexes with PML and mediates p53 deacetylation, thus protecting cells from senescence. SIRT1 represses muscle differentiation by two different mechanisms that involve MyoD: (i) in co-operation with PCAF and (ii) by deacetylating Lys⁴²⁴ of MEF2, which promotes its sumoylation by HDAC4, leading to suppression of myogenic genes. SIRT1 interacts with PPAR-γ and aP2 promoters, as well as with the PPAR-γ cofactors NcoR and SMRT to inhibit adipogenesis. Interactions of SIRT1 with BCL11A or Hes1/Hey2, and SIRT2 with the homeobox transcription factor, HOXA10, may regulate development. Glucose metabolism and energy modulated through deacetylation of PCG-1α and transcriptional repression of UCP2 respectively. SIRT6 mainly localizes to heterochromatin to regulate base excision repair, and SIRT2 shuffles from the cytoplasm to the nucleus during mitosis, where it deacetylates Lys¹⁶ of histone H4. In the nucleolus, SIRT7 activates RNA Pol I transcription, whereas SIRT1 represses it by deacetylating TAF_I68. Cytoplasmic SIRT1 and mitochondrial SIRT3 deacetylate and activate AceCS1 and AceCS2 respectively. SIRT4 mono-ADP-ribosylates GDH, which inhibits amino-acid-stimulated insulin secretion. AC, acetylation.

Figure 5. SIRT1 in regulating apoptosis and cell survival

Different apoptotic and cell survival pathways regulated by SIRT1. Refer to the text for details. Whether or not SIRT1 is a tumour suppressor or oncogene in vivo is, as yet, unclear.

Figure 6. SIRT1 and SIRT2 localize differentially in the brain

Immunofluorescence microscopy using specific SIRT1 and SIRT2 antibodies in cortex, hippocampus and striatum. SIRT1 (green) co-localizes with the neuronal marker NeuN (red) and DAPI (4′,6-diamidino-2-phenylindole; blue) in cortical neurons, hippocampal granular neurons and striatal neurons, while SIRT2 does not co-label with NeuN (neuron-specific nuclear-proteins) or DAPI; it mainly co-localizes with the fibres of myelinated axons in white matter and oligodendrocytes. Samples were processed as described previously [141].