title: SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets.
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.
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hajmrle
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mourad
authors.initials: M
authors.lastname: Ferdaoussi
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Plummer
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Spigelman
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Krista
authors.initials: K
authors.lastname: Lai
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada pmacdonald@ualberta.ca.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D015536:Down-Regulation; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D034622:RNA Interference; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: C508585:IL1B protein, human; D007328:Insulin; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases
keywords: SENP1; SUMOylation; inducible nitric oxide synthase; islets of Langerhans; sentrin/SUMO-specific protease 1