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Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes
- Source :
- Diabetes, 67(4), 687-696, 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, vol. 67, no. 4, pp. 687-696 . https://doi.org/10.2337/db17-0021
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Signal peptide
Preproinsulin
Endocrinology, Diabetes and Metabolism
HLA-A24 Antigen
Human leukocyte antigen
In Vitro Techniques
Protein Sorting Signals
Endoplasmic Reticulum
Aminopeptidases
Epitope
Cell Line
HLA-A11 Antigen
Minor Histocompatibility Antigens
Epitopes
Gene Knockout Techniques
03 medical and health sciences
Risk Factors
HLA-A2 Antigen
Internal Medicine
Aspartic Acid Endopeptidases
Humans
Insulin
Genetic Predisposition to Disease
Protein Precursors
HLA-A Antigens
Chemistry
Antigen processing
Endoplasmic reticulum
Transporter associated with antigen processing
Protective Factors
Cell biology
Protein Transport
Diabetes Mellitus, Type 1
030104 developmental biology
HLA-B Antigens
Signal peptide peptidase
T-Lymphocytes, Cytotoxic
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Diabetes, 67(4), 687-696, 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, vol. 67, no. 4, pp. 687-696 . https://doi.org/10.2337/db17-0021
- Accession number :
- edsair.doi.dedup.....d873924642ea5d31f0268e7d9e0658b6