SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells

Abstract

Insulin secretion from pancreatic ß cells is a multistep process that requires the coordination of exocytotic proteins that integrate diverse signals. These include signals derived from metabolic control of post-translational SUMOylation and depolarization-induced rises in intracellular Ca2+. Here we show that tomosyn, which suppresses insulin exocytosis by binding syntaxin1A, does so in a manner which requires its SUMOylation. Glucose-dependent de-SUMOylation of tomosyn1 at K298 releases syntaxin1A and controls the amplification of exocytosis in concert with a recently-identified tomosyn1-interacting partner; the Ca2+-binding protein secretagogin, which dissociates from tomosyn1 in response to Ca2+-raising stimuli and is required for insulin granule trafficking and exocytosis downstream of Ca2+ influx. Together our results suggest that tomosyn acts as a key signaling hub in insulin secretion by integrating signals mediated by metabolism-dependent de-SUMOylation and electrically-induced entry of Ca2+ to regulate the availability of exocytotic proteins required for the amplification of insulin secretion.

Improved glucose tolerance with DPPIV inhibition requires β‐cell SENP1 amplification of glucose‐stimulated insulin secretion

“…In fact, these ‘metabolic amplification’ pathways may act early to set the amplitude of glucose‐induced secretory responses – and reduced efficacy of this pathway may contribute to impaired insulin secretion in type 2 diabetes (T2D) (Grespan et al, 2018). One important pathway that contributes to the metabolic amplification of insulin secretion links the mitochondrial export of (iso)citrate and cytosolic generation of NADPH (Joseph et al, 2006; Ronnebaum et al, 2006) which facilitates insulin exocytosis (Ivarsson et al, 2005; Reinbothe et al, 2009) via the deSUMOylating enzyme sentrin‐specific protease‐1 (SENP1) (Ferdaoussi et al, 2015) acting on proteins at the exocytotic site (Dai et al, 2011; Ferdaoussi et al, 2017).…”

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

“…My group and others have also shown that SUMOylation regulates exocytotic membrane fusion [14,23], and this appears to be mediated by direct SUMOylation of exocytotic proteins and consequent regulation of protein-protein interactions amongst members of the secretory machinery [21]. Intriguingly, SUMOylation is suggested to both increase and decrease exocytosis (for a review, see [24]).…”

“…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]. Conversely, upregulating Senp1 causes impaired insulin secretion while inducing beta cell apoptosis and sensitising to IL-1β-induced islet dysfunction and death [19].…”

“…My group has proposed that insulin secretion is amplified in part by the mitochondrial export of reducing equivalents which act via a classical glutathione-glutaredoxin 1 (GSH-GRX1) signalling pathway to reduce SENP1 thiol groups, increasing its catalytic activity [18]. This deSUMOylates exocytotic proteins to release the SUMO brake on insulin exocytosis [14,21]. Effectively, this metabolism-driven redox-SENP1 pathway plays an important role controlling the magnitude of insulin secretory responses, depending on the metabolic state of the beta cell.…”

SCGN Administration prevents Insulin Resistance and Diabetic Complications in High-Fat Diet Fed Animals

“…In this line, we noticed Secretagogin (SCGN; a six-EF hand Ca 2+ -binding protein) as an intriguing prospect. This is based on the facts that in pancreatic β-cells, SCGN regulates both the insulin expression (6) and the release (6)(7)(8)(9)(10). Moreover, SCGN seems to be synchronously secreted with insulin upon cAMP stimulation (11).…”