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

Nat Commun. 2020 Jan 15;11(1):296. doi: 10.1038/s41467-019-14004-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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