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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 296 (01 15 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 31941883 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Iron-Sulfur Proteins
• RNA, Transfer, Lys
• Proinsulin
• Iron
• tRNA Methyltransferases
• CDKAL1 protein, mouse
• Ireb2 protein, mouse
• Iron Regulatory Protein 2

Topics

• Animals
• Cell Line, Tumor
• Glucose Intolerance (genetics)
• Homeostasis
• Insulin (metabolism)
• Insulin-Secreting Cells (metabolism)
• Insulinoma (genetics, metabolism)
• Iron (metabolism)
• Iron Regulatory Protein 2 (genetics, metabolism)
• Iron-Sulfur Proteins (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Pancreatic Neoplasms (genetics, metabolism)
• Proinsulin (genetics, metabolism)
• RNA, Transfer, Lys (genetics, metabolism)
• Rats
• Unfolded Protein Response (genetics)
• tRNA Methyltransferases (genetics, metabolism)