Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes . Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the hereditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C- terminal binding site. Positively regulates T and B cell proliferation through iron uptake . Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway . When dietary levels of stearate (C18:0) are low, promotes activation of the JNK pathway, resulting in HUWE1- mediated ubiquitination and subsequent degradation of the mitofusin MFN2 and inhibition of mitochondrial fusion . When dietary levels of stearate are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 ; (Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus.