Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification
Name
s41467-019-14004-5.pdf
Description
Published version
Size
3.67 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Santos, Maria C. Ferreira dos
Anderson, Cole P.
Neschen, Susanne
Zumbrennen-Bullough, Kimberly B.
Romney, Steven J.
Kahle-Stephan, Melanie
Rathkolb, Birgit
Gailus-Durner, Valerie
Fuchs, Helmut
Wolf, Eckhard
Date Issued
January 2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Ferreira dos Santos, Maria C. et al. "Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification." Nature Communications 11, 1 (January 2020): 296 © 2020 The Author(s)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-019-14004-5
