RT Journal Article
SR Electronic
T1 Citrullinated Glucose-Regulated Protein 78 Is an Autoantigen in Type 1 Diabetes
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 573
OP 586
DO 10.2337/db14-0621
VO 64
IS 2
A1 Rondas, Dieter
A1 Crèvecoeur, Inne
A1 D’Hertog, Wannes
A1 Ferreira, Gabriela Bomfim
A1 Staes, An
A1 Garg, Abhishek D.
A1 Eizirik, Decio L.
A1 Agostinis, Patrizia
A1 Gevaert, Kris
A1 Overbergh, Lut
A1 Mathieu, Chantal
YR 2015
UL http://diabetes.diabetesjournals.org/content/64/2/573.abstract
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.