Moonlighting cell surface GAPDH recruits Apo Transferrin to effect iron egress from mammalian cells

Abstract

Iron homeostasis is a tightly regulated process with precise control of its influx and egress from cells. Though mechanisms of its import into cells via 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) Earlier studies have revealed that, iron depleted cells recruit Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a moonlighting protein to their surface for internalization of the iron carrier holo transferrin (holo Tf). Here we report that under the contrary condition of intracellular iron excess, cells switch the isoform of GAPDH on their surface which now recruits iron free apo transferrin in close association with ferroportin to facilitate efflux of iron. Increased surface GAPDH expression synchronized with increased apo Tf 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 apo transferrin receptor, our work uncovers two-way switching of multifunctional molecules for managing cellular micronutrient requirements.