Regulation of Gluconeogenesis by a Novel Protein Phosphatase
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Gluconeogenesis is a biochemical process through which the organs or cells can synthesize glucose from non-carbohydrate carbon substrates and is important for blood glucose homeostasis. Multiple enzymes participate in this process. Among these enzymes, PEPCK1 and G6PC are the two most important rate-limiting enzymes. Given the key roles of PEPCK1 and G6PC in gluconeogenesis, expression of these two genes is regulated by multiple transcription factors. FoxO1 and FoxO3a are the two members of FoxO family that is involved in the regulation of PEPCK1 and G6PC expressions. The subcellular localization and transcription activity of FoxO1/3a are tightly regulated by their phosphorylation status. Akt is an important regulator of FoxO1/3a through phosphorylating FoxO1/3a at the key serine/threonine residues. MAPK phosphatase 3 can promote gluconeogenesis by dephosphorylating FoxO1 in mouse liver and PP2A was reported to be a phosphatase which can dephosphorylate FoxO1/3a in vitro and in cells. The nuclear localized phosphatase, which can regulate FoxO1/3a function on gluconeogenesis, is not found yet. Based on microarray database, we targeted a small C-terminal phosphatase as a potential FoxOs phosphatase. The role of this phosphatase was verified by using in vitro dephosphorylating and binding assay, cell based biochemistry and immunofluorescence assay, and knock out mouse model. In our study, we identified SMP5 as a new FoxO1/3a phosphatase. We showed that SMP5 co-localized and interacted with FoxO1/3a in the nucleus. SMP5 dephosphorylates FoxO1/3a in ser256/253, respectively. We also found that SMP5 facilitates FoxO1/3a nuclear localization and enhances their transcriptional activities. SMP5 KO mice have severe hypoglycemia and died within 24 hours after birth. FoxO1 and FoxO3a phosphorylation are increased. Thus, our findings indicate SMP5 is a FoxO1/3a phosphatase which controls their phosphorylation and nuclear localization, and in turn regulates their transcription activities on PEPCK1 and G6PC expression. Our study presents novel insights into the regulation of FoxO1/3a transcription activities by a new phosphatase during glucose homeostasis.