Looking for putative functions of the Leishmania cytosolic SIR2 deacetylase

During the past few years, the silent information regulator SIR2 protein family has attracted great interest due to its implication in an organism's life span extension. They bear diverse subcellular localization and play a role in transcriptional silencing and DNA repair. The biochemical reaction catalysed by these enzymes (nicotinamide adenine dinucleotide-dependant deacetylase/adenosine diphosphate-ribosyl transferase) is supposed to be linked to metabolism. Members of this protein family were described in parasitic organisms, but little information is available on potential functions of such enzymes in these organisms. In this article, we review recent information on structure and peculiar functions of SIR2s in eukaryotes, with emphasis on parasitic protozoa, particularly the Trypanosomatidae. Through the enzyme localization and the diverse substrates and by-products of the enzymatic reactions, we approach the potential pathways in which the Leishmania cytosolic SIR2 protein can be involved. The silent information regulator (SIR) proteins were first described as a set of non-essential genes, required in trans for the transcriptional repression of the silent mating type loci HML and HMR in budding yeast (Rine and Herskowitz 1987; Ivy et al. 1986; Klar et al. 1981a,b). Four groups were defined in the initial screen, called SIR1-4, encoding interacting proteins sharing no structural homology. SIR2 is unique among these factors in that it belongs to a large family of closely related nicotinamide adenine dinucleotide (NAD)-dependant deacetylase/adenosine diphosphate (ADP)-ribosyl transferase enzymes present in both prokaryotic and eukaryotic species (reviewed in Dutnall and Pillus 1981). In the budding yeast and in other eukaryotes, studies on SIR2 bearing nuclear localization have led to the general conclusion that SIR2 is a limiting component of longevity: deletions of SIR2 shorten life span, whereas addition of an extra copy increases it (Kaeberlein et al. 1999; Tissenbaum and Guarente 2001; Rogina and Helfand 2004). Therefore, SIR2s were proposed as regulators of life span by caloric restriction (Guarente 2005). Because of the central role of oxidation-reduction reactions in metabolism played by NAD and nicotinamide adenine dinucleotide (reduced form; NADH), enzymatic activity of SIR2 immediately connected SIR2-related proteins to metabolism. This function can be important for parasitic organism because they have to adapt to various nutritional conditions. In the malaria protozoan parasite Plasmodium, PfSIR2 (a nuclear SIR2 protein) was shown to be involved in var gene silencing. Survival of malaria protozoan parasite in the mammalian host is constantly challenged by host immune response, and most species of malaria have developed a process called clonal antigenic variation, which allows parasites to overcome immune destruction by periodically changing antigenic phenotype at the surface of parasitized erythrocytes. Multicopy gene families encoding antigenic surface determinants in human malaria species, Plasmodium falciparum (var gene family), are dispersed over the 14 chromosomes and map predominantly to telomere-associated regions in all studied Plasmodium species. Two distinct chromatin modifications led to the silencing of var genes. One of them is heterochromatin formation that involves a SIR2-like protein (Freitas Jr et al. 2005; Duraisingh et al. 2005). In Trypanosoma brucei, TbSIR2RP1 is a chromosome-associated NAD-dependant enzyme catalysing both deacetylation and ADP ribosylation. The level of expression of this enzyme iscorrelated to the level of resistance to DNA damage (Garcia-Salcedo et al. 2003). In Leishmania, SIR2RP1 (LmSIR2) was the first SIR2 deacetylase described to be present in cytoplasmic granules of yet unknown nature or in excreted/secreted materials (Zemzoumi et al. 1998; Sereno et al. 2005). Surprisingly, LmSIR2RP1 was found to be essential for the survival and/or proliferation of the parasite (Vergnes et al. 2005). However, the biological functions of SIR2RP1 await further investigations. In this review, through the enzyme localization and the diverse substrates and by-products of the deacetylase reaction, we approach the potential pathways in which the Leishmania cytosolic SIR2 protein can be involved.