Abstract
Posttranslational modifications of self-proteins play a substantial role in the initiation or propagation of the autoimmune attack in several autoimmune diseases, but their contribution to type 1 diabetes is only recently emerging. In the current study, we demonstrate that inflammatory stress, induced by the cytokines interleukin-1β and interferon-γ, leads to citrullination of GRP78 in β-cells. This is coupled with translocation of this endoplasmic reticulum chaperone to the β-cell plasma membrane and subsequent secretion. Importantly, expression and activity of peptidylarginine deiminase 2, one of the five enzymes responsible for citrullination and a candidate gene for type 1 diabetes in mice, is increased in islets from diabetes-prone nonobese diabetic (NOD) mice. Finally, (pre)diabetic NOD mice have autoantibodies and effector T cells that react against citrullinated GRP78, indicating that inflammation-induced citrullination of GRP78 in β-cells generates a novel autoantigen in type 1 diabetes, opening new avenues for biomarker development and therapeutic intervention.