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Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2.
Cremer, Tom; Hoelen, Hanneke; van de Weijer, Michael L; Janssen, George M; Costa, Ana I; van Veelen, Peter A; Lebbink, Robert Jan; Wiertz, Emmanuel J H J.
Afiliación
  • Cremer T; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Hoelen H; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
  • van de Weijer ML; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Janssen GM; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
  • Costa AI; Department of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
  • van Veelen PA; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Lebbink RJ; Department of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
  • Wiertz EJHJ; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proinsulina / Autoantígenos / Enzimas Ubiquitina-Conjugadoras / Degradación Asociada con el Retículo Endoplásmico / Proteolisis Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proinsulina / Autoantígenos / Enzimas Ubiquitina-Conjugadoras / Degradación Asociada con el Retículo Endoplásmico / Proteolisis Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos