Post-translational 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 ER stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, up-regulation 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 NFκB, 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 NFκB. Taken together, these findings identify SUMO1 as a novel anti-apoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation.
- Islets of Langerhans
- Copyright © 2014, American Journal of Physiology - Endocrinology and Metabolism