Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Hanneke Hoelen, Arnaud Zaldumbide, Wouter F van Leeuwen, Ellen C W Torfs, Marten A Engelse, Chopie Hassan, Robert Jan Lebbink, Eelco J de Koning, Maaike E Resssing, Arnoud H de Ru, Peter A van Veelen, Rob C Hoeben, Bart O Roep, Emmanuel J H J Wiertz

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)e0128206
JournalPLoS One
Volume10
Issue number6
DOIs
Publication statusPublished - 2015

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