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Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

Author

Listed:
  • Maria C. Ferreira dos Santos

    (University of Utah
    University of Utah)

  • Cole P. Anderson

    (University of Utah
    University of Utah
    Landstuhl Regional Medical Center)

  • Susanne Neschen

    (Helmholtz Zentrum München
    German Center for Diabetes Research (DZD))

  • Kimberly B. Zumbrennen-Bullough

    (University of Utah
    University of Utah)

  • Steven J. Romney

    (University of Utah
    University of Utah
    Thermo Fisher Scientific)

  • Melanie Kahle-Stephan

    (Helmholtz Zentrum München
    Medizinische Hochschule Brandenburg Theodor Fontane Institut für Sozialmedizin und Epidemiologie)

  • Birgit Rathkolb

    (Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München)

  • Valerie Gailus-Durner

    (Helmholtz Zentrum München)

  • Helmut Fuchs

    (Helmholtz Zentrum München)

  • Eckhard Wolf

    (Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München)

  • Jan Rozman

    (Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Martin Hrabe Angelis

    (Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Technische Universität München)

  • Weiling Maggie Cai

    (National University of Singapore
    Singapore-MIT Alliance for Research and Technology, 1 CREATE Way
    Agilent Technologies)

  • Malini Rajan

    (University of Utah
    University of Utah)

  • Jennifer Hu

    (Massachusetts Institute of Technology
    Celgene Corporation)

  • Peter C. Dedon

    (Singapore-MIT Alliance for Research and Technology, 1 CREATE Way
    Massachusetts Institute of Technology)

  • Elizabeth A. Leibold

    (University of Utah
    University of Utah
    University of Utah)

Abstract

Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe–S cluster biosynthesis, reducing the function of Cdkal1, an Fe–S cluster enzyme that catalyzes methylthiolation of t6A37 in tRNALysUUU to ms2t6A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms2t6A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2−/− β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.

Suggested Citation

  • Maria C. Ferreira dos Santos & Cole P. Anderson & Susanne Neschen & Kimberly B. Zumbrennen-Bullough & Steven J. Romney & Melanie Kahle-Stephan & Birgit Rathkolb & Valerie Gailus-Durner & Helmut Fuchs , 2020. "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14004-5
    DOI: 10.1038/s41467-019-14004-5
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