1. Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2.
- Author
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Cremer, Tom, Hoelen, Hanneke, van de Weijer, Michael L., Janssen, George M., Costa, Ana I., van Veelen, Peter A., Lebbink, Robert Jan, and Wiertz, Emmanuel J. H. J.
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PROTEOLYSIS , *UBIQUITIN-conjugating enzymes , *PROINSULIN , *TYPE 1 diabetes , *INSULIN - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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