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STAT3 as Longevity Protein Partner

Acetylation of the transcription factor STAT3 by the longevity-promoting protein SirT1 contributes to control of gluconeogenesis in response to nutrients. The sirtuin protein SirT1 is the focus of much attention because it can promote increased organismal life span and also because it functions in signaling pathways that regulate metabolism in response to nutrient sensing. SirT1 is a protein deacetylase, and in fasted animals it deacetylates transcription factors, thus promoting expression of genes encoding proteins that function in gluconeogenesis. Nie et al. now report that it has a second, apparently complementary, action to promote gluconeogenesis by inhibiting activity of the cytokine-regulated transcription factor STAT3 (signal transducer and activator of transcription 3). STAT3 itself inhibits expression of gluconeogenic genes and is subject to acetylation, so Nie et al. explored a possible regulatory interaction between SirT1 and STAT3. They showed that, in mouse liver cells, inhibition of SirT1 activity with pharmacological inhibitors or antisense oligonucleotides increased acetylation and phosphorylation of STAT3. Mouse embryo fibroblasts from SirT1 knockout animals also showed increased acetylation and phosphorylation of STAT3. Immunoprecipitation studies showed that endogenous STAT3 and SirT1 interacted in mouse liver cells and that the interaction was increased in fasted animals. Transcriptional regulation by STAT3 was also reduced in cells overexpressing SirT1. By mass spectrometry, Nie et al. identified three new lysine residues of STAT3 and confirmed two sites identified previously. Mutagenesis experiments indicated that the sites are required for regulation of transcriptional function of STAT3. Studies with knockout mice lacking STAT3 in the liver confirmed increased gluconeogenesis and showed that, in this model, promotion of hepatic gluconeogenesis by SirT1 in response to nutrients required STAT3. The authors suggest that STAT3, like Sirt1, may thus be important in metabolic homeostasis, control of organismal life span, and effects of diseases such as diabetes. Y. Nie, D. M. Erion, Z. Yuan, M. Dietrich, G. I. Shulman, T. L. Horvath, Q. Gao, STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat. Cell Biol. 11, 492–500 (2009). [PubMed]