A Sweet New Role for Ubiquitin-Specific Protease 2 in Controlling Hepatic Gluconeogenesis

Abstract

Hepatic glucose production is critical for maintaining normoglycemia during periods of nutrient deprivation, and dysregulation of hepatic gluconeogenesis is integral to the development of diabetic hyperglycemia. In recent decades, the signaling cascades downstream of the principal physiologic stimuli that suppress (insulin) or induce (glucagon and glucocorticoids) gluconeogenesis have been examined in detail. These signaling pathways can affect glucose production at multiple regulatory levels, including by covalent modification of enzymes involved in glucose and glycogen metabolism, alterations in regulatory metabolite concentrations, and by transcriptional regulation of gluconeogenic enzymes to control the capacity for glucose production. Given that hepatic glucose metabolism is tightly regulated and important for the survival of the organism, it is not surprising that several complex and elegant mechanisms of gluconeogenic control have emerged. It has been known for some time that attachment of several molecules of ubiquitin, a small 8.5 kDa protein, to other proteins regulates protein activity and stability, often by targeting the protein for proteasomal degradation (1). Ubiquitination of proteins is mediated by E3 ubiquitin ligases, while a large number of ubiquitin-specific proteases are known to act as deubiquinases. Recent studies have suggested that the process of ubiquitin-mediated proteasomal degradation is a regulated step in controlling gluconeogenesis. The cAMP response element-binding protein–regulated transcriptional coactivator 2 (CRTC2) is a critical regulator of gluconeogenic enzyme expression (2). CRTC2 phosphorylation by the insulin signaling cascade leads …