1. Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
- Author
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Santos MCFD, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, Rathkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, de Angelis MH, Cai WM, Rajan M, Hu J, Dedon PC, and Leibold EA
- Subjects
- Animals, Cell Line, Tumor, Glucose Intolerance genetics, Homeostasis, Insulin-Secreting Cells metabolism, Insulinoma genetics, Insulinoma metabolism, Iron Regulatory Protein 2 genetics, Iron-Sulfur Proteins metabolism, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Proinsulin genetics, Proinsulin metabolism, RNA, Transfer, Lys genetics, Rats, Unfolded Protein Response genetics, tRNA Methyltransferases genetics, Insulin metabolism, Iron metabolism, Iron Regulatory Protein 2 metabolism, RNA, Transfer, Lys metabolism, tRNA Methyltransferases metabolism
- 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 t
6 A37 in tRNALys UUU to ms2 t6 A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms2 t6 A37 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.- Published
- 2020
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