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Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes

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

In: Diabetes, Vol. 67, No. 4, 04.2018, p. 687-696.

Research output: Contribution to journalArticle

Harvard

Kronenberg-Versteeg, D, Eichmann, M, Russell, MA, de Ru, A, Hehn, B, Yusuf, N, van Veelen, PA, Richardson, SJ, Morgan, NG, Lemberg, MK & Peakman, M 2018, 'Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes', Diabetes, vol. 67, no. 4, pp. 687-696. https://doi.org/10.2337/db17-0021

APA

Kronenberg-Versteeg, D., Eichmann, M., Russell, M. A., de Ru, A., Hehn, B., Yusuf, N., van Veelen, P. A., Richardson, S. J., Morgan, N. G., Lemberg, M. K., & Peakman, M. (2018). Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes. Diabetes, 67(4), 687-696. https://doi.org/10.2337/db17-0021

Vancouver

Kronenberg-Versteeg D, Eichmann M, Russell MA, de Ru A, Hehn B, Yusuf N et al. Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes. Diabetes. 2018 Apr;67(4):687-696. https://doi.org/10.2337/db17-0021

Author

Kronenberg-Versteeg, Deborah ; Eichmann, Martin ; Russell, Mark A ; de Ru, Arnoud ; Hehn, Beate ; Yusuf, Norkhairin ; van Veelen, Peter A ; Richardson, Sarah J ; Morgan, Noel G ; Lemberg, Marius K ; Peakman, Mark. / Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes. In: Diabetes. 2018 ; Vol. 67, No. 4. pp. 687-696.

Bibtex Download

@article{c1dec4eb184f47fc92f62277b6ce4197,
title = "Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes",
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.",
author = "Deborah Kronenberg-Versteeg and Martin Eichmann and Russell, {Mark A} and {de Ru}, Arnoud and Beate Hehn and Norkhairin Yusuf and {van Veelen}, {Peter A} and Richardson, {Sarah J} and Morgan, {Noel G} and Lemberg, {Marius K} and Mark Peakman",
note = "{\textcopyright} 2018 by the American Diabetes Association.",
year = "2018",
month = apr,
doi = "10.2337/db17-0021",
language = "English",
volume = "67",
pages = "687--696",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "4",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes

AU - Kronenberg-Versteeg, Deborah

AU - Eichmann, Martin

AU - Russell, Mark A

AU - de Ru, Arnoud

AU - Hehn, Beate

AU - Yusuf, Norkhairin

AU - van Veelen, Peter A

AU - Richardson, Sarah J

AU - Morgan, Noel G

AU - Lemberg, Marius K

AU - Peakman, Mark

N1 - © 2018 by the American Diabetes Association.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

U2 - 10.2337/db17-0021

DO - 10.2337/db17-0021

M3 - Article

C2 - 29343547

VL - 67

SP - 687

EP - 696

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -

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