Regulation of TfR expression

The mechanisms underlying endocytosis and recycling of the TfR have been extensively studied and indeed, the TfR constitutes the most accepted marker for recycling endosomes. Diferric transferrin binds to the TfR and this complex is rapidly endocytosed via coated pits and from there it is transferred via early endosomes to recycling endosomes (Figure 2). Here,

Cell type

Expression

Unstimulated

Stimulated (stimulus)

Bone marrow CD34nlgh CD34med CD34'°" Cultured endothelial cells Peripheral blood T cells Peripheral blood B cells Peripheral blood NK cells Peripheral blood monocytes Peripheral blood eosinophils Peripheral blood neutrophils Platelets

Cultured fibroblasts

(thrombin)

"Expression ranged from none (-) to all cells brightly stained with anti-TfR (++++)

"Stimuli used were: tumor necrosis factor <x (TNFa), phytohemagglutinin (PHA), Staphylococcus aureus Cowan strain (SAC), interleukin 2 or 1 (IL-

2, IL-1), formyl-methionyl-leucyl-phenylalanine (fMLP).

Figure 2 Endocytosis of the TfR. Upon binding, the holotransferrin/TfR complex is internalized in clathrin-coated pits (CCP) which detach completely from the plasma membrane (PM) as clathrin-coated vesicles (CCV), and then, become un-coated and fuse with a tubulovesicular compartment, early endo-somes (EE). From early endosomes the complex is transferred to another tubulated compartment called recycling endosomes (RE) where under the low intraluminal pH conditions, iron is released to the cytosol to be captured by ferritin. The resulting apotransferrin/TfR complex remains associated and is recycled to the plasma membrane in exocytic vesicles. On the cell surface, under neutral pH conditions, apotransferrin dissociates from the TfR and both become ready to initiate a new cycle.

Figure 2 Endocytosis of the TfR. Upon binding, the holotransferrin/TfR complex is internalized in clathrin-coated pits (CCP) which detach completely from the plasma membrane (PM) as clathrin-coated vesicles (CCV), and then, become un-coated and fuse with a tubulovesicular compartment, early endo-somes (EE). From early endosomes the complex is transferred to another tubulated compartment called recycling endosomes (RE) where under the low intraluminal pH conditions, iron is released to the cytosol to be captured by ferritin. The resulting apotransferrin/TfR complex remains associated and is recycled to the plasma membrane in exocytic vesicles. On the cell surface, under neutral pH conditions, apotransferrin dissociates from the TfR and both become ready to initiate a new cycle.

under low pH conditions, transferrin releases iron but remains associated to the TfR. The TfR/ apotransferrin complex is recycled to the cell surface where, at neutral pH, apotransferrin dissociates from the receptor. Endocytosis of the TfR depends on a tetrapeptide sequence, YTRF, in its cytoplasmic tail. This sequence forms a tight turn and promotes endocytosis by binding to a complex of proteins known as adaptins which link the TfR tail to clathrin tri-skelions.

The expression of the TfR is also controlled at the translational level by the intracellular concentrations of iron. The 3' untranslated region of the TfR mRNA contains an iron-responsive element (IRE) which is also found in the 5' region of the ferritin mRNA. Under low intracellular iron concentrations, an IRE-binding protein (IRP) interacts with TfR's mRNA and inhibits its degradation, whereas the interaction with the 5' element in ferritin inhibits its translation. Both effects tend to increase the concentration of intracellular iron. Under high iron concentrations, IRP dissociates from IREs and the system is set for increased storage and reduced uptake of iron. In addition to iron concentration, other factors affect the level of TfR expression. In hematopoietic cells, interleukin 2 (IL-2), IL-6, cyclic nucleotides, phorbol esters, vitamin D and interferons regulate it. Thus, interferon y (IFN7) decreases TfR expression in macrophages; and IFNp, but nor IFN-y, has been described to inhibit TfR expression during in vitro differentiation of monocytes to macrophages. Some of these cytokines (tumor necrosis factor a (TNFa), IFN7) increase nitric oxide (NO) production that in turn may regulate TfR expression by increasing the affinity of IRP for IRE, independently of intracellular iron concentrations.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment