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Diabetes. 2011 Mar;60(3):838-47. doi: 10.2337/db10-0440. Epub 2011 Jan 24.

SUMOylation regulates insulin exocytosis downstream of secretory granule docking in rodents and humans.

Author information

1
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.

Abstract

OBJECTIVE:

The reversible attachment of small ubiquitin-like modifier (SUMO) proteins controls target localization and function. We examined an acute role for the SUMOylation pathway in downstream events mediating insulin secretion.

RESEARCH DESIGN AND METHODS:

We studied islets and β-cells from mice and human donors, as well as INS-1 832/13 cells. Insulin secretion, intracellular Ca(2+), and β-cell exocytosis were monitored after manipulation of the SUMOylation machinery. Granule localization was imaged by total internal reflection fluorescence and electron microscopy; immunoprecipitation and Western blotting were used to examine the soluble NSF attachment receptor (SNARE) complex formation and SUMO1 interaction with synaptotagmin VII.

RESULTS:

SUMO1 impairs glucose-stimulated insulin secretion by blunting the β-cell exocytotic response to Ca(2+). The effect of SUMO1 to impair insulin secretion and β-cell exocytosis is rapid and does not require altered gene expression or insulin content, is downstream of granule docking at the plasma membrane, and is dependent on SUMO-conjugation because the deSUMOylating enzyme, sentrin/SUMO-specific protease (SENP)-1, rescues exocytosis. SUMO1 coimmunoprecipitates with the Ca(2+) sensor synaptotagmin VII, and this is transiently lost upon glucose stimulation. SENP1 overexpression also disrupts the association of SUMO1 with synaptotagmin VII and mimics the effect of glucose to enhance exocytosis. Conversely, SENP1 knockdown impairs exocytosis at stimulatory glucose levels and blunts glucose-dependent insulin secretion from mouse and human islets.

CONCLUSIONS:

SUMOylation acutely regulates insulin secretion by the direct and reversible inhibition of β-cell exocytosis in response to intracellular Ca(2+) elevation. The SUMO protease, SENP1, is required for glucose-dependent insulin secretion.

PMID:
21266332
PMCID:
PMC3046844
DOI:
10.2337/db10-0440
[Indexed for MEDLINE]
Free PMC Article
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