Cells respond to iron deficiency through a well-characterized homeostatic response involving the RNA-binding proteins IRP1 and IRP2. Marina Bayeva et al. now reveal additional complexity to this response, identifying a new regulator, the protein tristetraprolin (TTP, Cell Metab. 16, 645–657).
TTP is a mammalian homolog of RNA-binding proteins in baker's yeast that regulate iron homeostasis by destabilizing the mRNAs of iron-requiring proteins. The authors showed that TTP deficiency in mammalian cells made them more vulnerable to iron deprivation. Iron deprivation or inhibition of the kinase mTOR led to increased TTP expression, which in turn reduced the expression of specific mRNAs containing its target sequence. Unexpectedly, TTP bound and destabilized the mRNA of transferrin receptor 1 (TfR1), thereby inhibiting cellular iron uptake. TTP thus seems to act in opposition to the IRP1–IRP2 pathway, which stabilizes TfR1 mRNA, and the authors propose that in this way TTP may block excessive iron import. They then extended their cellular data to mice, showing that the hearts of mice lacking TTP had increased TfR1 expression.
It remains to be seen how this newly identified mTOR–TTP pathway might affect the dysregulation of iron homeostasis that occurs in individuals treated with mTOR inhibitors, such as rapamycin, or in a wide variety of disease states.
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Basson, M. Fine-tuning iron. Nat Med 18, 1753 (2012). https://doi.org/10.1038/nm.3037