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

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, Eckhard Wolf, Jan Rozman, Martin Hrabe Angelis, Weiling Maggie Cai, Malini Rajan, Jennifer Hu, Peter C. Dedon and Elizabeth A. Leibold ()
Additional contact information
Maria C. Ferreira dos Santos: University of Utah
Cole P. Anderson: University of Utah
Susanne Neschen: Helmholtz Zentrum München
Kimberly B. Zumbrennen-Bullough: University of Utah
Steven J. Romney: University of Utah
Melanie Kahle-Stephan: Helmholtz Zentrum München
Birgit Rathkolb: Helmholtz Zentrum 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
Martin Hrabe Angelis: Helmholtz Zentrum München
Weiling Maggie Cai: National University of Singapore
Malini Rajan: University of Utah
Jennifer Hu: Massachusetts Institute of Technology
Peter C. Dedon: Singapore-MIT Alliance for Research and Technology, 1 CREATE Way
Elizabeth A. Leibold: University of Utah

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14004-5

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