Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2.

Autor: Cremer T; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands., Hoelen H; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., van de Weijer ML; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom., Janssen GM; Department of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., Costa AI; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., van Veelen PA; Department of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands., Lebbink RJ; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Wiertz EJHJ; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 May 24; Vol. 19 (5), pp. e0287877. Date of Electronic Publication: 2024 May 24 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0287877
Abstrakt: Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation and subsequent presentation of the PPIB10-18 autoantigen. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future T1D therapies.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Cremer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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