Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes (PubMed:26214738). 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 heditary 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 (PubMed:26642240). Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway (PubMed:26214738). 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 (PubMed:26214738). When dietary levels of stearate (C18:0) are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 (PubMed:26214738). (Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus. Homodimer; disulfide-linked. Binds one transferrin or HFE molecule per subunit. Binds the HLA class II histocompatibility antigen, DR1. Interacts with SH3BP3. Interacts with STEAP3; facilitates TFRC endocytosis in erythroid precursor cells (PubMed:26642240). (Microbial infection) Interacts with Guanarito, Junin and Machupo arenavirus glycoprotein complex (PubMed:17287727, PubMed:18268337). Identified by mass spectrometry in melanosome fractions from stage I to stage IV. Regulated by cellular iron levels through binding of the iron regulatory proteins, IRP1 and IRP2, to iron-responsive elements in the 3'-UTR. Up-regulated upon mitogenic stimulation. Stearoylated by ZDHHC6 which inhibits TFRC-mediated activation of the JNK pathway and promotes mitochondrial fragmentation (PubMed:26214738). Stearoylation does not affect iron uptake (PubMed:26214738). N- and O-glycosylated, phosphorylated and palmitoylated. The serum form is only glycosylated. Proteolytically cleaved on Arg-100 to produce the soluble serum form (sTfR). Palmitoylated on both Cys-62 and Cys-67. Cys-62 seems to be the major site of palmitoylation. The disease is caused by variants affecting the gene represented in this entry. Serum transferrin receptor (sTfR) is used as a means of detecting erythropoietin (EPO) misuse by athletes and as a diagnostic test for anemia resulting from a number of conditions including rheumatoid arthritis, pregnancy, irritable bowel syndrome and in HIV patients. Canine and feline parvoviruses bind human and feline transferrin receptors and use these receptors to enter and infect cells. Belongs to the peptidase M28 family. M28B subfamily.