Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
Maria C Ferreira Dos SantosCole P AndersonSusanne NeschenKimberly B Zumbrennen-BulloughSteven J RomneyMelanie Kahle-StephanBirgit RathkolbValérie Gailus-DurnerHelmut FuchsEckhard WolfJan RozmanMartin Hrabě de AngelisWeiling Maggie CaiMalini RajanJennifer HuPeter C DedonElizabeth A LeiboldPublished in: Nature communications (2020)
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.
Keyphrases
- iron deficiency
- type diabetes
- glycemic control
- induced apoptosis
- cardiovascular disease
- mass spectrometry
- cell cycle arrest
- ms ms
- binding protein
- insulin resistance
- amino acid
- metabolic syndrome
- protein protein
- single cell
- adipose tissue
- dna methylation
- gene expression
- small molecule
- cell proliferation
- room temperature
- skeletal muscle
- ionic liquid
- pi k akt