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Cited by 92Pancreatic function and diabetesCellular transport and secretionUbiquitin and proteasome pathways

SUMOylation Regulates Insulin Exocytosis Downstream of Secretory Granule Docking in Rodents and Humans

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Dai, Xiao-Qing, Plummer, Greg, Casimir, Marina, Kang, Youhou, Hajmrle, Catherine, Gaisano, Herbert Y., Manning Fox, Jocelyn E., MacDonald, Patrick E.·2011·Diabetes
DOI 10.2337/db10-0440PMC PMC3046844
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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 Ca2+, 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 Ca2+. 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 Ca2+ 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 Ca2+ elevation. The SUMO protease, SENP1, is required for glucose-dependent insulin secretion.

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  • The amplifying effect of glucose via desumoylation of synaptotagmin-7 can occur without physical translocation of secretory granules.

    “Notably, the amplifying effect of glucose (via desumoylation of synaptotagmin-7) can occur without physical translocation of secretory granules (136).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [136]

    The Results (‘SUMOylation increases granule docking and SNARE complex formation’; page unavailable) say SUMO1 does not inhibit secretion by reducing granule recruitment or docking, placing its effect downstream of docking. The Discussion reports that glucose transiently disrupts the SUMO1/synaptotagmin VII interaction and that SENP1 mimics glucose’s enhancement of exocytosis, but says the underlying mechanism remains to be elucidated. Thus the paper supports an effect downstream of granule translocation, not the definite claim that glucose acts via desumoylation of synaptotagmin-7. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Glucose increases exocytosis by NADPH-dependent activation of the deSUMOylating enzyme SENP-1.

    “Glucose increases exocytosis by NADPH-dependent activation of the deSUMOylating enzyme SENP-1 (136).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [136]

    The Results section reports that glucose enhances β-cell exocytosis and that SENP1 knockdown prevents this enhancement. The Discussion says SENP1 mimics glucose’s effect, but explicitly states that the underlying mechanism remains to be elucidated. Our copy does not establish NADPH-dependent activation of SENP1. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In both mouse and human β-cells, the modulation of exocytosis by glucose involves the reversible attachment of SUMO-1 to synaptotagmin-7.

    “In both mouse and human β-cells there is evidence that this modulation involves the reversible attachment of small ubiquitin-like modifier protein 1 (SUMO-1) to synaptotagmin-7.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [136]

    The Results section, “SUMO1 interacts dynamically with synaptotagmin VII” (page not provided), reports a SUMOylation-dependent interaction in rodent cells and human islets that is transiently disrupted by glucose. But the Discussion (page not provided) explicitly says further work is needed to determine whether SUMO1 is attached directly to synaptotagmin VII or to a binding partner. The evidence supports a reversible association, not the specified attachment. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

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Authors
Dai, X.-Q., Plummer, G., Casimir, M., Kang, Y., Hajmrle, C., Gaisano, H. Y., Manning Fox, J. E., & MacDonald, P. E.
Affiliations
  • University of Alberta (CA)
  • University of Toronto (CA)
  • Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Corresponding author
MacDonald, Patrick E.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-02-21
Volume
60
Issue
3
Pages
838-847
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db10-0440
PMC
PMC3046844
OpenAlex
W2140346195
Cited by
92
References
0
Citations by year
2025: 3 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 3 · 2013: 8 · 2012: 12
FWCI
7.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Canadian Diabetes Association
  • University of Alberta
  • Fondation pour la Recherche Médicale
  • Alberta Heritage Foundation for Medical Research
  • Alberta Diabetes Foundation
  • Canadian Institutes of Health Research (MOP86544, MOP-97845)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
SUMOylation, SUMO1, insulin secretion, synaptotagmin VII, SENP1, deSUMOylation, SNARE complex, calcium signaling, glucose-stimulated insulin secretion, pancreatic islets, INS-1 cells
MeSH terms
Insulin Secretion, Analysis of Variance, Animals, Calcium, Cells, Cultured, Cysteine Endopeptidases, Exocytosis, Glucose, Humans, Insulin, Microscopy, Electron, Endopeptidases, Blotting, Western, Secretory Vesicles, SUMO-1 Protein, Immunoprecipitation, Insulin-Secreting Cells, Synaptotagmins, Mice, HEK293 Cells, Sumoylation

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