Adaptive survival mechanism to glucose restrictions

Glucose is partly metabolized through the glucose sensing hexosamine biosynthetic pathway (HBP) leading to the formation of an end product called acetylated amino sugar nucleotide uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAC serves as a donor substrate during O-GlcNAcylation (O-linked β-N-acetylglucosamine or O-GlcNAc) [1]. Serine or threonine residues of nuclear and cytoplasmic proteins are directly O-GlcNAcylated, competing with phosphorylation. O-GlcNAcylation is catalyzed by one unique enzyme called O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). O-GlcNAcylation is cleaved and removed by another one enzyme called N-acetyl-β-D-glucosaminidase (OGA) [1]. The existence of single and unique enzymes (OGT and OGA) acting on various different substrates suggest that enzyme activity can be modulated by binding partners in response to glucose levels [1]. O-GlcNAcylation levels are very dynamic and cycles rapidly, fluctuating in response to glucose concentrations influencing cell signaling pathways [1]. O-GlcNAcylation is thus relevant to various chronic human diseases such as diabetes, cardiovascular and neurodegenerative disorders and cancer. For example, OGT promotes aneuploidy, regulates cell-cycling via HCF-1 cleavage, and participates in regulatory links between metabolic changes and carcinogenesis [2]. Changes in OGA or OGT activity and hence, in O-GlcNAcylation levels may occur in human breast cancer and hepatocellular carcinoma (HCC) tissues [1]. The oncoprotein c-MYC is also O-GlcNAcylated. c-MYC protein is very unstable; its levels and activity are regulated by ubiquitination and proteasomal degradation, initiated by its phosphorylation at Thr-58 by GSK3β. Thr-58 is an OGT target which regulates c-MYC stability. O-GlcNAcylation at Thr-58 stabilizes c-MYC, promoting tumorigenesis [1]. Unconventional prefoldin RPB5 interactor (URI) binds and modulates OGT activity in response to glucose concentrations. In presence of glucose, URI, OGT and protein phosphatase 1 gamma (PP1γ) form a heterotrimeric complex. Glucose deprivation induces anaplerotic reactions, increasing ATP/cAMP levels, thereby activating PKA which in turn, phosphorylates URI at Ser-371. Phosphorylated URI frees PP1γ from the heterotrimeric complex and, URI becomes a potent inhibitor of OGT [1]. PKA reportedly forms a mitochondrial complex with PP1 catalytic units and the pro-apoptotic Bcl-2-associated death promoter (BAD) that influences glucose homeostasis [3]. Thus, URI/OGT/PP1γ complex may integrate glucose metabolism, possibly through a mitochondrial supra-molecular complex including PKA and BAD [3,4]. Abnormal glucose metabolism and BAD requirement in glucose deprivation-induced death is reported in Bad knockout and non-phosphorylatable BAD(3SA) knockin mice [3,5]. BAD is thus an apoptotic sentinel that monitors glucose signaling. Notably, OGT overexpression in a transgenic mouse model yields a type 2 diabetes (T2D) phenotype with insulin resistance and hyperleptinemia [6]. Additionally, …