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 de Angelis, Weiling Maggie Cai, Malini Rajan, Jennifer Hu, Peter C. Dedon, Elizabeth A. Leibold

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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 tRNALys UUU 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.

Original languageEnglish
Article number296
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2020
Externally publishedYes


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