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- Title
Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97.
- Authors
Hoelen, Hanneke; Zaldumbide, Arnaud; van Leeuwen, Wouter F.; Torfs, Ellen C. W.; Engelse, Marten A.; Hassan, Chopie; Lebbink, Robert Jan; de Koning, Eelco J.; Resssing, Maaike E.; de Ru, Arnoud H.; van Veelen, Peter A.; Hoeben, Rob C.; Roep, Bart O.; Wiertz, Emmanuel J. H. J.
- Abstract
Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T-cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D.
- Subjects
PEOPLE with diabetes; CD8 antigen; AUTOANTIGENS; MOLECULAR genetics; GENE silencing
- Publication
PLoS ONE, 2015, Vol 10, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0128206