Journal Article

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

Anderson, Cole P., Zumbrennen-Bullough, Kimberly B., Rozman, Jan, Leibold, Elizabeth A., Neschen, Susanne, Hu, Jennifer, Dedon, Peter C., Romney, Steven J., Fuchs, Helmut, Wolf, Eckhard, Rajan, Malini, Kahle-Stephan, Melanie, Cai, Weiling Maggie, Gailus-Durner, Valerie, Rathkolb, Birgit, de Angelis, Martin Hrabe, Santos, Maria C. Ferreira dos

2020

Overview

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 tRNA Lys UUU to ms 2 t 6 A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms 2 t 6 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. Iron metabolism is linked to type 2 diabetes. Here the authors describe a mechanism through which cellular iron deficiency caused by loss of Irp2 impairs Cdkal1 function, resulting in inaccurate proinsulin translation, impaired proinsulin processing and reduced insulin secretion.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 14 / 14/1 / 14/32 / 14/63 / 38/77 / 38/88 / 38/90 / 631/80 / 631/80/304 / 64/60 / 82/1 / 82/29 / 82/51 / 96/106 / Animals / Beta cells / Biosynthesis / Cell Line, Tumor / Cellular manufacture / Clusters / Codons / Diabetes / Diabetes mellitus (non-insulin dependent) / Ferritin / Glucose Intolerance - genetics / Homeostasis / Humanities and Social Sciences / Insulin / Insulin - metabolism / Insulin secretion / Insulin-Secreting Cells - metabolism / Insulinoma - genetics / Insulinoma - metabolism / Iron / Iron - metabolism / Iron and steel making / Iron deficiency / Iron Regulatory Protein 2 - genetics / Iron Regulatory Protein 2 - metabolism / Iron-Sulfur Proteins - metabolism / Lysine / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Neurodegenerative diseases / Nutrient deficiency / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - metabolism / Post-transcription / Proinsulin - genetics / Proinsulin - metabolism / Proteins / Rats / RNA, Transfer, Lys - genetics / RNA, Transfer, Lys - metabolism / Science / Science (multidisciplinary) / Secretion / Transferrin / Transferrins / tRNA / tRNA Ala / tRNA Methyltransferases - genetics / tRNA Methyltransferases - metabolism / Unfolded Protein Response - genetics