Interestingly the subcellular localization of FBPase in

Interestingly, the subcellular localization of FBPase in hepatocytes and proximal tubule rgd peptide reveals that FBPase is also able to translocate to the nucleus in these cell types. The nuclear localization of muscle-FBPase was recently reported [35]. This data corroborate our results on the ability of liver FBPase to localize to the nuclei of liver and kidney cells. Nevertheless, the authors discussed that rat liver FBPase does not contain a nuclear localization sequence (NLS) compared to the muscle isoform [35]. We agree that liver FBPase does not contain this specific canonical NLS, but the nature of these signals is broad and liver FBPase may contain other NLSs or a bipartite signal. Moreover, using neural networks that predict subcellular location we found that liver FBPase contains other classical NLSs (PXKRXKX) [36], that may allow the translocation of FBPase into the nuclei. Which are the physiological reasons for the localization of FBPase inside the nuclei of kidney and liver cells? Broad evidence exists about the nuclear translocation and cytosolic redistribution of several enzymes in response to metabolic conditions [13], [14], [15], [37]. In the absence of glucose, GK is localized in the nucleus of the hepatocytes, bound to its regulatory protein, but moves into the cytoplasm when the levels of sugar increase [15], [38]. Muscular GS (M-GS) is also concentrated in the nucleus at low glucose and at high glucose concentrations translocates to the cytosol, where it adopts a particulate pattern [37]. The nuclear role of GK in response to high glucose concentration was proposed as a mechanism to minimize the futile cycle between glucose and glucose 6-phosphate, an event that represents an important mechanism for the regulation of glucose metabolism [38]. We can also suggest a similar mechanism for the nuclear localization of FBPase in the cell avoiding the formation of a futile cycle between F-6-P and Fru-1,6-P2, as well as the degradation of FBPase. Moreover, it is possible to postulate that other FBPase putative functions in the nuclei might be the participation of the enzyme as transcription factor, involvement in the phosphorylation/dephosphorylation process that regulates the activation of transcription factors, or participation in the DNA metabolism. These unusual ideas are supported by the demonstration that the glycolytic enzymes lactate dehydrogenase and 3-phosphoglycerate kinase can reside in the nuclei of mammalian cells and exert functions in DNA replication, transcription and DNA repair, in addition to their role as catalysts in the cytoplasm [13], [14], [39]. The transfer of these glycolytic enzymes to cell nuclei requires phosphorylation [39] and notably rat liver FBPase at the COOH terminus contains two AMP-dependent phosphorylation sites [40]. The catalytic cytosolic function is not altered by this modification; however, it can be responsible for the FBPase nuclear localization and also for the regulation of a new phosphatase function exerted by this enzyme in the nuclei.
Acknowledgements