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

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.

DOI: 10.1371/journal.pone.0128206

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@inproceedings{Hoelen2015ProteasomalDO, title={Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97}, author={Hanneke Hoelen and Arnaud Zaldumbide and Wouter F. van Leeuwen and Ellen C. W. Torfs and Marten A. Engelse and Chopie Hassan and Robert Jan Lebbink and Eelco J P de Koning and Maaike E. Resssing and Arnoud H. de Ru and Peter A. van Veelen and Rob C Hoeben and Bart O. Roep and Emmanuel J. H. J. Wiertz and Edda Fiebiger}, booktitle={PloS one}, year={2015} }