Citrullination of glucokinase is linked to autoimmune diabetes
Mei-Ling Yang, Sheryl Horstman, Renelle J. Gee, Perrin Guyer, TuKiet T. Lam, Jean Kanyo, Ana Luisa Perdigoto, Cate Speake, Carla J. Greenbaum, Aïsha Callebaut, Lut Overbergh, Richard G. Kibbey, Kevan C. Herold, Eddie A. James, Mark J. Mamula
Abstract
Abstract Inflammation, including reactive oxygen species and inflammatory cytokines in tissues amplify various post-translational modifications of self-proteins. A number of post-translational modifications have been identified as autoimmune biomarkers in the initiation and progression of Type 1 diabetes. Here we show the citrullination of pancreatic glucokinase as a result of inflammation, triggering autoimmunity and affecting glucokinase biological functions. Glucokinase is expressed in hepatocytes to regulate glycogen synthesis, and in pancreatic beta cells as a glucose sensor to initiate glycolysis and insulin signaling. We identify autoantibodies and autoreactive CD4 + T cells to glucokinase epitopes in the circulation of Type 1 diabetes patients and NOD mice. Finally, citrullination alters glucokinase biologic activity and suppresses glucose-stimulated insulin secretion. Our study define glucokinase as a Type 1 diabetes biomarker, providing new insights of how inflammation drives post-translational modifications to create both neoautoantigens and affect beta cell metabolism.