Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31941883.
- Also identified by DOI 10.1038/s41467-019-14004-5 and PMC identifier 6962211.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>6</sup>A37 in tRNA<sup>Lys</sup><sub>UUU</sub> to ms<sup>2</sup>t<sup>6</sup>A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms<sup>2</sup>t<sup>6</sup>A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2<sup>-/-</sup> 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.
Medical subject headings
- Insulin
- Iron
- Iron Regulatory Protein 2
- RNA, Transfer, Lys
- tRNA Methyltransferases