SUMOylation of Pancreatic Glucokinase Regulates Its Cellular Stability and Activity*

Abstract

Background: Glucokinase is a key player in carbohydrate metabolism, but how this enzyme is regulated by post-translational modifications is largely unknown. Results: Glucokinase is SUMO-modified in vitro and in pancreatic ␤-cells, increasing its activity and stability. Conclusion: SUMOylation of glucokinase is a novel form of modification, regulating its cellular stability and activity. Significance: SUMO conjugation of glucokinase may have an important regulatory function in pancreatic ␤-cells.

A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets

“…These observations are in line with what my laboratory [14,18,19] and others [12,20] have shown using complementary models, including in human islets. We know, for example, that increasing SUMOylation blunts glucose-stimulated insulin secretion by directly inhibiting insulin exocytosis [14,21], and that islet Senp1 knockout results in glucose intolerance without affecting islet mass or insulin content [18].…”

“…SUMOylation, and, in particular, the SUMO1 protein, was identified by multiple laboratories [10] and initially studied extensively as a regulator of transcription [11]. SUMOylation is now known to have well-defined roles outside the nucleus; for example in the regulation of glucokinase activity [12], mitochondrial dynamics [13] and exocytosis [14]. Knockout of Ubc9 or key SENP genes results in embryonic lethality [15].…”

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

“…Indeed, SENP1 alone can enhance insulin exocytosis, but this action is blocked under oxidizing conditions (32). SUMOylation may play diverse roles in pancreatic islet biology (33), having recently been implicated in metabolism (34), incretin receptor signaling (35), excitability (36), and survival (37). Importantly, the role for SENP1 in insulin secretion and in vivo glucose homeostasis remains to be resolved.…”

“…jci.org Volume 125 Number 10 October 2015 out of SENP1, and thus, the acute nature by which cSENP1 affects the amplification of exocytosis suggests a direct, rather than transcriptionally mediated, role in insulin secretion. SUMOylation also controls GLP-1 receptor signaling (35), islet survival (37), and glucokinase activity (34). While a role for SENP1 per se (as opposed to other SENPs) in these contexts remains to be investigated, here we have demonstrated a key role for SENP1 in the amplification of insulin exocytosis to control glucose homeostasis in four different models of SENP1 deficiency: by acute knockdown with siRNA in human β cells and by transduction of mouse Senp1 fl/fl β cells with Ad-Cre and in both tissue-selective (pSENP1-KO) and tissue-inducible (iβSENP1-KO) mouse models.…”

Pc2‐mediated SUMOylation of WWOX is essential for its suppression of DU145 prostate tumorigenesis

“…The SUMO modification also seems to affect subcellular localization and stability of target protein [19]. SUMOylation process requires three enzymatic action involving E1 activating enzyme, E2 conjugation enzyme Ubc9, and E3 ligase as well as SUMO proteins (SUMO1 and SUMO2/3) [20].…”