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

Ferreira dos Santos, Maria C.; Anderson, Cole P.; Neschen, Susanne; Zumbrennen-Bullough, Kimberly B.; Romney, Steven J.; Kahle-Stephan, Melanie; Rathkolb, Birgit; Gailus-Durner, Valerie; Fuchs, Helmut; Wolf, Eckhard; Rozman, Jan; Hrabe de Angelis, Martin; Cai, Weiling Maggie; Rajan, Malini; Hu, Jennifer; Dedon, Peter C.; Leibold, Elizabeth A. (2020): Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. In: Nature Communications, Vol. 11, No. 1, 296

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 beta 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(UUU)(Lys) 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(-/-) beta 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.

• Item Type: Journal article
• Faculties: Veterinary Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2041-1723
• Language: English