BioChem - DOS

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

PLoS ONE

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.

<P>Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic &beta;-cells. Recognition of these autoantigens by CD8<SUP>+</SUP> T cells results in the destruction of pancreatic &beta;-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of &beta;-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.</P>

2024

Public Library of Science

1932-6203

19

5

pp.e0287877

10.1371/journal.pone.0287877

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