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Am J Physiol Endocrinol Metab. 2014 Oct 15;307(8):E664-73. doi: 10.1152/ajpendo.00168.2014. Epub 2014 Aug 19.

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

Author information

1
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
2
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada pmacdonald@ualberta.ca.

Abstract

Posttranslational modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMO-specific proteases (SENPs). While increased SUMOylation reduces β-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca²⁺ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca²⁺ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of β-cell death, iNOS and NF-κB, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1β-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-κB. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation.

KEYWORDS:

SENP1; SUMOylation; inducible nitric oxide synthase; islets of Langerhans; sentrin/SUMO-specific protease 1

PMID:
25139051
PMCID:
PMC4200309
DOI:
10.1152/ajpendo.00168.2014
[Indexed for MEDLINE]
Free PMC Article

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