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

doi:10.1371/journal.pone.0128206

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

28 Citations (Scopus)

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 language	English
Pages (from-to)	e0128206
Journal	PLoS One
Volume	10
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0128206
Publication status	Published - 2015

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Hoelen, H., Zaldumbide, A., van Leeuwen, W. F., Torfs, E. C. W., Engelse, M. A., Hassan, C., Lebbink, R. J., de Koning, E. J., Resssing, M. E., de Ru, A. H., van Veelen, P. A., Hoeben, R. C., Roep, B. O., & Wiertz, E. J. H. J. (2015). Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97. PLoS One, 10(6), e0128206. https://doi.org/10.1371/journal.pone.0128206

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title = "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.",

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T1 - Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

AU - Hoelen, Hanneke

AU - Zaldumbide, Arnaud

AU - van Leeuwen, Wouter F

AU - Torfs, Ellen C W

AU - Engelse, Marten A

AU - Hassan, Chopie

AU - Lebbink, Robert Jan

AU - de Koning, Eelco J

AU - Resssing, Maaike E

AU - de Ru, Arnoud H

AU - van Veelen, Peter A

AU - Hoeben, Rob C

AU - Roep, Bart O

AU - Wiertz, Emmanuel J H J

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pone.0128206

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SN - 1932-6203

VL - 10

SP - e0128206

JO - PLoS One

JF - PLoS One

IS - 6

ER -

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

Abstract

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