Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2.
PLoS One
; 19(5): e0287877, 2024.
Article
en En
| MEDLINE
| ID: mdl-38787820
ABSTRACT
Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic ß-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic ß-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of ß-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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proinsulina
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Autoantígenos
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Enzimas Ubiquitina-Conjugadoras
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Degradación Asociada con el Retículo Endoplásmico
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Proteolisis
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article