Abstract

Autoimmune diseases such as lupus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (T1D) frequently target self proteins that undergo posttranslational protein modifications. Oxidative stress, which is implicated in the pathogenesis of T1D, leads to various protein modifications including isoaspartyl (isoAsp) and carbonyl formation. We have previously identified that isoAsp protein modification can trigger T cell autoimmunity in both human and murine models of lupus. However, the role of oxidative stress-induced posttranslational modifications in T1D is still poorly understood. Herein, we demonstrate that isoAsp modification and oxidative carbonylation accumulate in pancreas and/or pancreatic islet proteins from spontaneous diabetes-prone NOD mice. Specifically, isoAsp content were elevated in both target organ (pancreas) and peripheral erythrocytes of diabetic NOD mice compared to pre-diabetic NOD mice. Moreover, we identified the beta subunit of prolyl-4-hydroxylase (P4hb) as a protein that is abundantly carbonylated in pancreatic islet. Sera from NOD mice and early onset diabetic patients contain antibodies that recognized isoAsp- and/or carbonyl-modified pancreas proteins including P4hb protein. These studies provide a novel insight into the mechanism of breaking immune tolerance and the diagnostic and/or therapeutic targets associated with isoAsp and carbonylated posttranslational protein modifications in T1D.

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