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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620611
Title:
Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.
Authors:
Kronenberg-Versteeg, D.; Eichmann, M.; Russell, M. A.; de Ru, A.; Hehn, B.; Yusuf, N.; van Veelen, P. A.; Richardson, S. J.; Morgan, Noel; Lemberg, M. K.; Peakman, M.
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.
Citation:
Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes. 2018 Diabetes
Publisher:
American Diabetes Association
Journal:
Diabetes
Issue Date:
17-Jan-2018
URI:
http://hdl.handle.net/11287/620611
DOI:
10.2337/db17-0021
PubMed ID:
29343547
Additional Links:
http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=29343547
Type:
Journal Article
Language:
en
ISSN:
1939-327X
Appears in Collections:
Honorary contracts publications; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorKronenberg-Versteeg, D.en
dc.contributor.authorEichmann, M.en
dc.contributor.authorRussell, M. A.en
dc.contributor.authorde Ru, A.en
dc.contributor.authorHehn, B.en
dc.contributor.authorYusuf, N.en
dc.contributor.authorvan Veelen, P. A.en
dc.contributor.authorRichardson, S. J.en
dc.contributor.authorMorgan, Noelen
dc.contributor.authorLemberg, M. K.en
dc.contributor.authorPeakman, M.en
dc.date.accessioned2018-02-13T15:01:44Z-
dc.date.available2018-02-13T15:01:44Z-
dc.date.issued2018-01-17-
dc.identifier.citationMolecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes. 2018 Diabetesen
dc.identifier.issn1939-327X-
dc.identifier.pmid29343547-
dc.identifier.doi10.2337/db17-0021-
dc.identifier.urihttp://hdl.handle.net/11287/620611-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=29343547en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleMolecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.en
dc.typeJournal Articleen
dc.identifier.journalDiabetesen
dc.type.versionIn press (epub ahead of print)en

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