mTOR regulates cellular iron homeostasis through tristetraprolin

Cell Metab. 2012 Nov 7;16(5):645-57. doi: 10.1016/j.cmet.2012.10.001. Epub 2012 Oct 25.


Iron is an essential cofactor with unique redox properties. Iron-regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron-requiring genes in both mammalian and yeast cells, and modulates survival in low-iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron-regulatory pathways, and point toward the existence of a yeast-like TTP-mediated iron conservation program in mammals.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Gene Expression / drug effects
  • Iron / metabolism*
  • Mice
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism
  • Tristetraprolin / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • CTH1 protein, S cerevisiae
  • DNA-Binding Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Transferrin
  • Saccharomyces cerevisiae Proteins
  • TIS11 protein, S cerevisiae
  • Tfrc protein, mouse
  • Transcription Factors
  • Tristetraprolin
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Iron
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Sirolimus