Casey et al. (1988) analyzed the regulation by iron of the TFRC gene by examining mouse cells transformed with chimeric constructs containing the human transferrin receptor gene's promoter and either the structural gene for bacterial chloramphenicol acetyltransferase or the human TFRC cDNA. They concluded that at least 2 genetic elements, one 5-prime and one 3-prime to the gene, are involved in the regulation of the TFRC gene by iron.

Radoshitzky et al. (2007) demonstrated a specific high-affinity association between TFR1 and the entry glycoprotein of Machupo virus (a New World arenavirus). Expression of human TFR1, but not human TFR2 (604720), in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the glycoprotein of Machupo, Guanarito, and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TFR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin, and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. Radoshitzky et al. (2007) concluded that TFR1 is a cellular receptor for New World hemorrhagic fever arenaviruses.

Ishii et al. (2009) found that knockdown of Ppargc1b (608886) in primary mouse osteoclasts impaired their differentiation and mitochondrial biogenesis. Transferrin receptor expression was induced in osteoclasts via iron regulatory protein-2 (IREB2; 147582), and Tfrc-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, which was associated with the induction of mitochondrial respiration, production of reactive oxygen species, and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected female mice against bone loss following estrogen deficiency resulting from ovariectomy. Ishii et al. (2009) concluded that mitochondrial biogenesis, which is induced by PPARGC1B and supported by TFRC-mediated iron uptake for utilization by mitochondrial respiratory proteins, is fundamental to osteoclast activation and bone metabolism.

Elahi et al. (2013) showed that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after coculture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2 (ARG2; 107830), and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with L-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses, parallels the loss of suppression and restored resistance to the perinatal pathogens Listeria monocytogenes and E. coli. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Elahi et al. (2013) thus concluded that CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. The authors further suggested that this finding challenged the idea that the susceptibility of neonates to infection reflects immune cell-intrinsic defects and instead highlights processes that are developmentally more essential and that inadvertently mitigate innate immune protection.

Senyilmaz et al. (2015) identified the metabolite stearic acid (C18:0) and human TFR1 as mitochondrial regulators. Senyilmaz et al. (2015) elucidated a signaling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK (601158) signaling. This leads to reduced ubiquitination of mitofusin via HUWE1 (300697), thereby promoting mitochondrial fusion and function. Senyilmaz et al. (2015) found that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink (608309) or Parkin (602544) in Drosophila. Senyilmaz et al. (2015) concluded that their work identified the metabolite C18:0 as a signaling molecule regulating mitochondrial function in response to diet.

Gruszczyk et al. (2018) identified TFR1 as the receptor for P. vivax reticulocyte-binding protein 2b (PvRB2b) and determined the structure of the N-terminal domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TFR1 recognition. Gruszczyk et al. (2018) validated TFR1 as the biologic target of PvRBP2b engagement by means of TFR1 expression knockdown analysis. TFR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax but not to invasion of P. falciparum.