DeSUMOylation Controls Insulin Exocytosis in Response to Metabolic Signals

Abstract

The secretion of insulin by pancreatic islet β-cells plays a pivotal role in glucose homeostasis and diabetes. Recent work suggests an important role for SUMOylation in the control of insulin secretion from β-cells. In this paper we discuss mechanisms whereby (de)SUMOylation may control insulin release by modulating β-cell function at one or more key points; and particularly through the acute and reversible regulation of the exocytotic machinery. Furthermore, we postulate that the SUMO-specific protease SENP1 is an important mediator of insulin exocytosis in response to NADPH, a metabolic secretory signal and major determinant of β-cell redox state. Dialysis of mouse β-cells with NADPH efficiently amplifies β-cell exocytosis even when extracellular glucose is low; an effect that is lost upon knockdown of SENP1. Conversely, over-expression of SENP1 itself augments β-cell exocytosis in a redox-dependent manner. Taken together, we suggest that (de)SUMOylation represents an important mechanism that acutely regulates insulin secretion and that SENP1 can act as an amplifier of insulin exocytosis.

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

“…The redox sensitivity of SENP1 has been ascribed to key thiols on cysteine 603 (the catalytic residue conserved in all SENPs) and cysteine 613 (unique to SENP1 and SENP5), which we find are required for amplification of exocytosis. A role for the redox-dependent regulation of SENP1 is supported by the opposing actions of H 2 O 2 and GSH/GRX1 on SENP1 activity observed in vitro and our previous finding that oxidation prevents the SENP1-dependent amplification of exocytosis (32).…”

“…The SUMO1 peptide can block insulin exocytosis at a distal step (30), and intriguingly, the activity of SENP1 may be redox sensitive (31), suggesting that it could transduce the GSH/GRX1 signal. 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).…”

“…Thus, we propose ( Figure 8H) that glucose stimulation amplifies the secretory response through a pathway that requires the ICDc-dependent generation of NADPH and GSH, which is coupled to enhanced Ca 2+ -dependent exocytosis by SENP1. Impairment of this signaling pathway in T2D could occur in several ways: (a) reduced mitochondrial function, leading to lowered isocitrate export and cytosolic NADPH production; (b) oxidative stress and redirection of NADPH, GSH, and GRX1 into a protective function; or (c) direct oxidative inactivation of SENP1 (32). That dysfunction in β cells from donors with T2D can be circumvented by reintroduction of isocitrate-to-SENP1 pathway intermediates suggests that the exocytotic mechanism remains intact and could be harnessed for alternative therapeutic approaches to increase insulin secretion in T2D.…”

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

“…Upregulation of SUMO1 decreases insulin gene expression (28,44), glucagon-like peptide-1 (GLP-1) receptor signaling (42), and both glucose-and exendin-4-stimulated insulin secretion (10,42), suggesting that deSUMOylation may improve secretory function. Indeed, knockdown of the SUMOylating enzyme Ubc9 enhances exendin-4-stimulated insulin secretion (42), and upregulation of the deSUMOylating enzyme SENP1 increases exocytosis from rodent ␤-cells at low glucose (10,48). Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10).…”

“…Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10). Thus, while increased SUMOylation results in secretory impairment (10,42,48), the effect of the deSUMOylating enzyme SENP1 remains unknown.…”