Citrullination of glucokinase is linked to autoimmune diabetes

• Published in: Nature communications Vol. 13; no. 1; pp. 1870 - 11
• Main Authors: Yang, Mei-Ling, Horstman, Sheryl, Gee, Renelle, Guyer, Perrin, Lam, TuKiet T., Kanyo, Jean, Perdigoto, Ana L., Speake, Cate, Greenbaum, Carla J., Callebaut, Aïsha, Overbergh, Lut, Kibbey, Richard G., Herold, Kevan C., James, Eddie A., Mamula, Mark J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14/1; 14/19; 631/250; 631/250/38; 692/163; 692/163/2743/137/1418; 82/29; 82/51; 82/58; Animals; Autoantibodies; Autoimmune diseases; Autoimmunity; Beta cells; Biomarkers; CD4 antigen; Citrullination; Citrulline; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; Epitopes; Glucokinase; Glucokinase - genetics; Glucose; Glucose - metabolism; Glycogen; Glycogens; Glycolysis; Hepatocytes; Humanities and Social Sciences; Humans; Inflammation; Inflammation - metabolism; Insulin; Insulin - metabolism; Insulin secretion; Liver - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred NOD; multidisciplinary; Pancreas; Post-translation; Proteins; Reactive oxygen species; Science; Science (multidisciplinary); Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29512-0

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. Post translational modifications are involved in the regulation of a number of proteins and can be themselves modified by the cellular environment. Here the authors implicate citrullination of glucokinase in autoimmune diabetes