Molecular pathways for immune recognition of preproinsulin signal peptide in type 1 diabetes
The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated HLA-B*1801 and HLA-B*3906 (ris...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
April 2018
|
| In: |
Diabetes
Year: 2018, Volume: 67, Issue: 4, Pages: 687-696 |
| ISSN: | 1939-327X |
| DOI: | 10.2337/db17-0021 |
| Online Access: | Verlag, Volltext: https://doi.org/10.2337/db17-0021 Verlag: https://diabetes.diabetesjournals.org/content/67/4/687 
|
| Author Notes: | 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 |
| Summary: | The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles, revealing that four of six alleles present epitopes derived from the signal peptide region. During cotranslational 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), ER-luminal epitopes, which are TAP independent, each presented by different HLA class I molecules and N-terminal trimmed by ER aminopeptidase 1 for optimal presentation. In vivo, TAP expression is significantly upregulated and correlated with HLA class I hyperexpression 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. |
|---|---|
| Item Description: | Gesehen am 30.10.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1939-327X |
| DOI: | 10.2337/db17-0021 |