Citrullination of glucokinase is linked to autoimmune diabetes

Mei-Ling Yang, Sheryl Horstman, Renelle Gee, Perrin Guyer, TuKiet T. Lam, Jean Kanyo, Ana L. Perdigoto, Cate Speake, Carla J. Greenbaum, Aïsha Callebaut, Lut Overbergh, Richard G. Kibbey, Kevan C. Herold, Eddie A. James and Mark J. Mamula ()
Additional contact information
Mei-Ling Yang: Yale University
Sheryl Horstman: Benaroya Research Institute at Virginia Mason
Renelle Gee: Yale University
Perrin Guyer: Benaroya Research Institute at Virginia Mason
TuKiet T. Lam: Yale University
Jean Kanyo: Keck MS & Proteomics Resource, WM Keck Foundation Biotechnology Resource Laboratory
Ana L. Perdigoto: Yale University
Cate Speake: Benaroya Research Institute at Virginia Mason
Carla J. Greenbaum: Benaroya Research Institute at Virginia Mason
Aïsha Callebaut: KU Leuven
Lut Overbergh: KU Leuven
Richard G. Kibbey: Yale University
Kevan C. Herold: Yale University
Eddie A. James: Benaroya Research Institute at Virginia Mason
Mark J. Mamula: Yale University

Nature Communications, 2022, vol. 13, issue 1, 1-11

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.

Date: 2022
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DOI: 10.1038/s41467-022-29512-0

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