title: Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition.
abstract: BACKGROUND
  The long held view is that mammalian cells obtain transferrin (Tf) bound iron utilizing specialized membrane anchored receptors. Here we report that, during increased iron demand, cells secrete the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which enhances cellular uptake of Tf and iron.
  
  
  METHODS
  These observations could be mimicked by utilizing purified GAPDH injected into mice as well as when supplemented in culture medium of model cell lines and primary cell types that play a key role in iron metabolism. Transferrin and iron delivery was evaluated by biochemical, biophysical and imaging based assays.
  
  
  RESULTS
  This mode of iron uptake is a saturable, energy dependent pathway, utilizing raft as well as non-raft domains of the cell membrane and also involves the membrane protein CD87 (uPAR). Tf internalized by this mode is also catabolized.
  
  
  CONCLUSIONS
  Our research demonstrates that, even in cell types that express the known surface receptor based mechanism for transferrin uptake, more transferrin is delivered by this route which represents a hidden dimension of iron homeostasis.
  
  
  CONCLUSIONS
  Iron is an essential trace metal for practically all living organisms however its acquisition presents major challenges. The current paradigm is that living organisms have developed well orchestrated and evolved mechanisms involving iron carrier molecules and their specific receptors to regulate its absorption, transport, storage and mobilization. Our research uncovers a hidden and primitive pathway of bulk iron trafficking involving a secreted receptor that is a multifunctional glycolytic enzyme that has implications in pathological conditions such as infectious diseases and cancer.
authors.affiliation: Institute of Microbial Technology, CSIR, Chandigarh, India.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Sheokand
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Himanshu
authors.initials: H
authors.lastname: Malhotra
authors.forename: Vikas
authors.initials: V
authors.lastname: Tillu
authors.forename: Chaaya Iyengar
authors.initials: CI
authors.lastname: Raje
authors.forename: Manoj
authors.initials: M
authors.lastname: Raje
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001693:Biological Transport, Active / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011990:Receptors, Transferrin; D055293:Receptors, Urokinase Plasminogen Activator; D014168:Transferrin; D007501:Iron; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases