Posttranslational modifications of proteins in type 1 diabetes: the next step in finding the cure?

Abstract

The overall role of modification of β-cell antigens in type 1 diabetes has not been elucidated and was the focus of a recent workshop on posttranslational modification of proteins in type 1 diabetes. The prevailing opinion of the workshop attendees was that novel insights into the mechanism of loss of immune tolerance might be gained and that novel diagnostic and therapeutic approaches could be developed for type 1 diabetes if protein modifications were shown to play a critical role in the disease.

FIG. 1.

A possible role for PTMs in the pathogenesis of type 1 diabetes. Any form of nonspecific β-cell stress such as inflammation or metabolic stress may lead to alterations in peptide/protein state. These altered peptides/proteins may be processed by the immune system in different immunogenic ways. A: Modifications such as phosphorylation, methylation, or glycosylation may create a new epitope for autoantibody binding. Alternatively, after uptake by APCs, the PTM may create a different nontolerized ligand for T-cell recognition. B: Enzymatic or spontaneous modifications, such as deamidation and citrullination, can also generate neoepitopes or influence antigen processing. C: Extracellular proteolysis to generate peptide fragments may be required to allow subsequent modification. In this case, the posttranslationally modified protein (yellow star) forms part of a neoepitope for T-cell recognition. Alternatively, the PTM itself could enhance or limit extracellular degradation by interference with the cleavage site. Figure adapted from Anderton et al. (43).

FIG. 2.

The value of studying PTMs in type 1 diabetes. Discovering the role of PTMs in altering β-cell proteins may not only lead to better understanding of the pathogenesis of type 1 diabetes but could also open avenues for the development of new diagnostic and therapeutic tools for prevention and intervention in the disease.