title: Moonlighting cell-surface GAPDH recruits apotransferrin to effect iron egress from mammalian cells.
abstract: Iron (Fe(2+), Fe(3+)) homeostasis is a tightly regulated process, involving precise control of iron influx and egress from cells. Although the mechanisms of its import into cells by iron carrier molecules are well characterized, iron export remains poorly understood. The current paradigm envisages unique functions associated with specialized macromolecules for its cellular import (transferrin receptors) or export (ferroportin, also known as SLC40A1). Previous studies have revealed that iron-depleted cells recruit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multitasking, 'moonlighting' protein, to their surface for internalization of the iron carrier holotransferrin. Here, we report that under the converse condition of intracellular iron excess, cells switch the isoform of GAPDH on their surface to one that now recruits iron-free apotransferrin in close association with ferroportin to facilitate the efflux of iron. Increased expression of surface GAPDH correlated with increased apotransferrin binding and enhanced iron export from cells, a capability lost in GAPDH-knockdown cells. These findings were confirmed in vivo utilizing a rodent model of iron overload. Besides identifying for the first time an apotransferrin receptor, our work uncovers the two-way switching of multifunctional molecules to manage cellular micronutrient requirements.
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036.
authors: Navdeep
authors: N
authors: Sheokand
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036.
authors: Himanshu
authors: H
authors: Malhotra
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036.
authors: Santosh
authors: S
authors: Kumar
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036.
authors: Vikas A
authors: VA
authors: Tillu
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036.
authors: Anoop S
authors: AS
authors: Chauhan
authors: National Institute of Pharmaceutical Education and Research, Phase X, Sector 67, SAS Nagar, Punjab, INDIA-160062.
authors: Chaaya I
authors: CI
authors: Raje
authors: Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, INDIA-160036 manoj@imtech.res.in.
authors: Manoj
authors: M
authors: Raje
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000378:metabolism*; D005290:Ferric Compounds / Q000378:metabolism*; D005296:Ferrous Compounds / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014168:Transferrin / Q000378:metabolism*
chemical_list: D001059:Apoproteins; D005290:Ferric Compounds; D005296:Ferrous Compounds; D014168:Transferrin; C028284:apotransferrin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
keywords: Apotransferrin; Ferroportin; GAPDH; Higher order multifunctional protein; Iron export; Receptor