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Citrullination of glucokinase is linked to autoimmune diabetes

Author

Listed:
  • 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
    Keck MS & Proteomics Resource, WM Keck Foundation Biotechnology Resource Laboratory)

  • 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
    Yale University)

  • Kevan C. Herold

    (Yale University
    Yale University)

  • Eddie A. James

    (Benaroya Research Institute at Virginia Mason)

  • Mark J. Mamula

    (Yale University)

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.

Suggested Citation

  • 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 & , 2022. "Citrullination of glucokinase is linked to autoimmune diabetes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29512-0
    DOI: 10.1038/s41467-022-29512-0
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