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Original Research
Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes
Deborah Kronenberg-Versteeg, Martin Eichmann, Mark A. Russell, Arnoud de Ru, Beate Hehn, Norkhairin Yusuf, Peter A. van Veelen, Sarah J. Richardson, Noel G. Morgan, Marius K. Lemberg and Mark Peakman
Diabetes 2018 Jan; db170021. https://doi.org/10.2337/db17-0021
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Abstract

The signal peptide region of preproinsulin (PPI) contains epitopes targeted by human leucocyte antigen-A (HLA-A)-restricted (HLA-A0201, A2402) cytotoxic T-cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended PPI epitope discovery to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles revealing that 4/6 alleles present epitopes derived from the signal peptide region. During co-translational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical, proteasome-directed pathway. Using in vitro translocation assays with specific inhibitors and gene knockout in PPI-expressing target cells we show that PPI signal peptide antigen processing requires signal peptide peptidase (SPP). The intramembrane protease SPP generates cytoplasm-proximal epitopes, which are transporter-associated-with–antigen-processing (TAP)-dependent, and ER-luminal (TAP-independent) epitopes, each presented by different HLA class I molecules, and N-terminal trimmed by ER aminopeptidase 1 (ERAP1) for optimal presentation. In vivo, TAP expression is significantly up-regulated and correlated with HLA class I hyper-expression in insulin-containing islets of patients with type 1 diabetes. Thus, PPI signal peptide epitopes are processed by SPP and loaded for HLA-guided immune recognition via pathways that are enhanced during disease pathogenesis.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0021.

  • Received January 5, 2017.
  • Accepted January 9, 2018.
  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes
Deborah Kronenberg-Versteeg, Martin Eichmann, Mark A. Russell, Arnoud de Ru, Beate Hehn, Norkhairin Yusuf, Peter A. van Veelen, Sarah J. Richardson, Noel G. Morgan, Marius K. Lemberg, Mark Peakman
Diabetes Jan 2018, db170021; DOI: 10.2337/db17-0021

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Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes
Deborah Kronenberg-Versteeg, Martin Eichmann, Mark A. Russell, Arnoud de Ru, Beate Hehn, Norkhairin Yusuf, Peter A. van Veelen, Sarah J. Richardson, Noel G. Morgan, Marius K. Lemberg, Mark Peakman
Diabetes Jan 2018, db170021; DOI: 10.2337/db17-0021
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© 2019 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.