mTOR Regulates Cellular Iron Homeostasis through Tristetraprolin

Abstract

SUMMARY 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 towards the existence of a yeast-like TTP-mediated iron conservation program in mammals.

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

“…[23][24][25][26][27][28][29] Normally, an increase in cellular iron inactivates iron regulatory proteins and decreases TfR1 mRNA levels. We observed increased TfR1 mRNA levels and a concurrent cellular iron overload with HIV infection, which suggests that HIV infection is driving the upregulation of TfR1 independent of other cellular iron regulatory machineries.…”

Deficiency of the placenta- and yolk sac-specific tristetraprolin family member ZFP36L3 identifies likely mRNA targets and an unexpected link to placental iron metabolism

“…Nonetheless, the Tfrc transcript was stabilized in the ZFP36L3-deficient TSCs, its 3′UTR contains two highly conserved and closely spaced 8-mer potential ZFP36L3-binding sites, and it was highly enriched in the ZFP36L3 immunoprecipitates. It was previously identified as a possible direct TTP target in other tissues (Bayeva et al, 2012). These data suggest that the profound decrease in Tfrc mRNA levels might be a secondary effect of ZFP36L3 deficiency resulting in inhibition of transcription of Tfrc in the placenta.…”

Therapeutic Potential of Everolimus on Core Autism Symptoms and Increasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis

“…Previous studies have reported that increased intracellular copper levels suppressed mTOR signaling [44], and that copper treatment down regulated mTOR signaling [45]. With respect to increased serum Tf levels, the mTOR signaling pathway modulates Tf uptake [10], and mTOR regulates iron homeostasis through the Tf receptor [9]. Additionally, the Tf receptor may be useful for measuring intracellular changes in mTOR activity [46].…”

“…Oxidative stress-induced reactive oxygen species [7] enhanced mTOR [5], and that mTOR inhibitor everolimus blocked the enhanced phosphorylation of mTOR [6]. Moreover, copper-related antioxidants, such as ceruloplasmin (Cp) [8] and iron-related transferrin (Tf) [9] are closely related to mTOR signaling. For example, Cp expression mas related to activation of mTOR pathway [8].…”