| Sir2 proteins are a group of phylogenetically conserved deacetylases that play a role in chromatin remodeling, transcriptional regulation, and control of biological processes such as DNA damage repair, circadian rhythm, and oxidative metabolism. The mammalian Sir2 homologue, Sirtuin 1 (SIRT1), mediates this wide array of cellular responses through deacetylation of select transcriptional regulators, including the coactivator, peroxisome proliferator activated receptor gamma 1 alpha (PGC-1alpha). However, despite a continually growing list of downstream targets, the upstream pathways and factors controlling SIRT1 function remain unclear. I show here that SIRT1 catalytic activity can he modulated by fluctuations in the intracellular concentration of the Sirtuin cofactor, nicotinamide adenine dinucleotide (NAD+), which result from changing nutrient availability or ectopic expression of NAD+ biosynthetic enzymes. Additionally, I identify a novel protein kinase A (PKA)-dependent phosphorylation on a highly conserved serine residue in the SIRT1 deacetylase domain that rapidly increases intrinsic enzymatic efficiency independently of changes in NAD+. Taken together, both nutrient sensing (i.e. NAD+ levels) and cAMP cascades (i.e. PKA phosphorylation) dually regulate SIRT1 activity and subsequent control of transcriptional networks linked to fatty acid oxidation and energy expenditure. This work demonstrates a novel convergence of two important signaling pathways responsible for stress responses and the maintenance of energy homeostasis in mammals and expands the mechanistic understanding of Sirtuin regulation. |
