PT  - JOURNAL ARTICLE
AU  - Rondas, Dieter
AU  - Crèvecoeur, Inne
AU  - D’Hertog, Wannes
AU  - Ferreira, Gabriela Bomfim
AU  - Staes, An
AU  - Garg, Abhishek D.
AU  - Eizirik, Decio L.
AU  - Agostinis, Patrizia
AU  - Gevaert, Kris
AU  - Overbergh, Lut
AU  - Mathieu, Chantal
TI  - Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes
AID  - 10.2337/db14-0621
DP  - 2015 Feb 01
TA  - Diabetes
PG  - 573--586
VI  - 64
IP  - 2
4099  - http://diabetes.diabetesjournals.org/content/64/2/573.short
4100  - http://diabetes.diabetesjournals.org/content/64/2/573.full
SO  - Diabetes2015 Feb 01; 64
AB  - 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.