Protein & Peptide Letters, 2011, 18, 167-173 167 0929-8665/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. SIRT1 Deacetylase Activity and the Maintenance of Protein Homeostasis in Response to Stress: An Overview Jomar Patricio Monteiro 1 and Maria Isabel Nogueira Cano 1, * Departamento de Genética, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho - UNESP, Botucatu, SP, Brazil Abstract: The present review intends to summarize the, yet preliminary, but very important emerging data underlining the functions exerted by the nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase SIRT1 on protein homeostasis. The main focus of the discussion is the cooperation between SIRT1 and the heat shock factor 1 (HSF1) responsible for ac- tivating the transcription of molecular chaperones, the protein-protective factors that resolve damaged/misfolded and ag- gregated proteins generated by heat stress or metabolism. SIRT1, a mammalian ortholog of the yeast silent information regulator 2, is a stress activated protein deacetylase that contributes to life-span extension by regulating different cell sur- vival pathways, including replicative senescence, inflammation and resistance to hypoxic and heat stress. Phosphorylation is the major mechanism controlling the level and function of SIRT1 required for normal cell cycle progression and cell survival under stress conditions. Phosphorylated SIRT1 deacetylates and coactivates different substrates, including HSF1. Deacetylated HSF1 binds to the heat shock promoter element found upstream of genes encoding molecular chaperones. Overexpression of SIRT1 in cultured cells also helps them to survive exposure to heat stress. Conversely, its down- regulation accelerates the attenuation of the heat shock response promoting the release of HSF1 from its cognate promoter element. Very recently, in a mouse model for Alzheimer’s disease, SIRT1 deacetylase activity was also found activating the transcription of -secretase, the enzyme responsible for inhibiting the formation of aggregates of neuronal -amyloid plaques. How SIRT1 activity protects cells from the deleterious effects of damaged/misfolded proteins and the implication of these findings on age-related pathologies are discussed. Keywords: Deacetylation, heat shock factor 1 (HSF1), molecular chaperones, protein homeostasis, sirtuin, SIRT1. THE SIRTUIN FAMILY AND THE IMPACT OF SIRT1 IN CELL SURVIVAL AND STRESS RESPONSE Sirtuins are a family of highly conserved proteins impli- cated in multiple pathways including gene control, aging, cell survival, metabolism, and DNA repair. They are acti- vated in the course of calorie restriction and stress, and show enhanced expression in genetically modified organisms with increased longevity [1]. The sirtuin family is defined by its homology with the budding yeast silent information regula- tor Sir2p, the founding member of this family, which partici- pates in different chromatin-associated functions [2]. In yeast, there are four Sir proteins that silence a variety of genes positioned at different chromosomal locations. Spe- cifically, Sir1p is required for silencing at HM loci but not telomeres. Sir2p, besides inducing silencing at HM loci and telomeres, is also able to repress gene expression and mitotic and meiotic intra-chromosomal recombination within rDNA clusters. Sir3p and Sir4p form a complex with Sir2 and are both required for gene silencing. Independent discoveries also indicated that yeast Sir2p has two apparently distinct enzymatic activities. It functions in vivo as a histone deacety- lase, which spreads along chromatin creating inactive do- mains and in vitro as an ADP-ribosyltransferase [3, 4]. *Address correspondence to this author at the Rua 02, s/no., Depto. De Genetica, IBB-UNESP, Botucatu, 18618-970, Rubiao Junior, Botucatu, Sao Paulo, Brazil; Tel: (+5514) 38116229; E-mail: micano@ibb.unesp.br In contrast to other classic deacetylases that use a zinc-catalyzed mechanism (i.e, histone deacetylases or HDACs), Sir2p requires NAD + for the deacetylation reac- tion. It catalyzes the hydrolysis of NAD + by transferring an acetyl moiety from acetyl lysine yielding nicotinamide, the unique metabolite O-acetyl ADP ribose and deacetylated lysines [1]. Sir2p probably works as a sensor of the cytosolic ratio of NAD + /NADH, since its function is associated with the metabolic and cellular energy states [1]. Sirtuin members are also relatively conserved and homo- logues of the yeast Sir2p are found in organisms such as bac- teria [5], protozoa [6], fly [7], worms [8] and mammals [9]. Based on their phylogenetic relationship, sirtuins can be grouped into more than a dozen classes and subclasses of proteins that are structurally defined by two central domains that together form a highly conserved catalytic core. In spite of this conservation, sirtuins can differ in their N and C termini domains, resulting in protein subgroups show- ing highly divergent subcellular localizations, expression patterns and biological functions [4]. In vertebrates, includ- ing humans, there are seven sirtuins, which were classified in SIRT1 to SIRT7, due to their cellular location. SIRT1 and SIRT6 are in the nucleoplasm, SIRT7 is in the nucleolus, SIRT2 in the cytoplasm, SIRT3 in the mitochondria and in the nucleus, and SIRT4 and SIRT5 in the mitochondria [10]. They also show preference for different substrates suggesting that they have acquired new specialized functions to match the increasing complexity of the organism [2, 4].