2.A.110 The Heme Transporter, Heme-Responsive Gene Protein (HRG) Family

Caenorhabditis elegans and human HRG-1-related proteins are conserved, membrane-bound permeases that bind and translocate heme in metazoan cells. Yuan et al. (2012) showed that cellular import of heme by HRG-1-related proteins from worms and humans require strategically located amino acids that are topologically conserved across species. The endosomal CeHRG-1 required both a specific histidine in the predicted second TMS and the FARKY motif in the C-terminal tail for heme transport. By contrast, the plasma membrane CeHRG-4 protein transports heme by utilizing a histidine in the exoplasmic (E2) loop and the FARKY motif. Optimal activity under heme limiting conditions, however, requires histidine in the E2 loop of CeHRG-1 and tyrosine in TMS2 of CeHRG-4. An analogous system exists in humans because mutation of the synonymous histidine in TMS2 of hHRG-1 eliminates heme transport activity, implying an evolutionarily conserved heme transport mechanism that predates vertebrate origins. These results support a model in which heme is translocated across membranes facilitated by conserved amino acids positioned on the exoplasmic, cytoplasmic, and transmembrane regions of HRG-1-related proteins (Yuan et al. 2012).

Adult humans have about 25 trillion red blood cells (RBCs), and each second they recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. White et al (2013) showed that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages caused attenuation of heme transport from the phagolysosomal compartment, and missense polymorphisms in human HRG1 proved to be defective in heme transport. The results revealed that human HRG1 is the long-sought heme transporter for heme-iron recycling in macrophages and suggested that genetic variations in HRG1 could be modifiers of human iron metabolism.

The reaction catalyzed by HRG1 is:

heme (lysosome) → heme (cytoplasm)



Huynh, C., X. Yuan, D.C. Miguel, R.L. Renberg, O. Protchenko, C.C. Philpott, I. Hamza, and N.W. Andrews. (2012). Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog 8: e1002795.

Miguel DC., Flannery AR., Mittra B. and Andrews NW. (2013). Heme uptake mediated by LHR1 is essential for Leishmania amazonensis virulence. Infect Immun. 81(10):3620-6.

Rajagopal, A., A.U. Rao, J. Amigo, M. Tian, S.K. Upadhyay, C. Hall, S. Uhm, M.K. Mathew, M.D. Fleming, B.H. Paw, M. Krause, and I. Hamza. (2008). Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453: 1127-1131.

Renberg, R.L., X. Yuan, T.K. Samuel, D.C. Miguel, I. Hamza, N.W. Andrews, and A.R. Flannery. (2015). The Heme Transport Capacity of LHR1 Determines the Extent of Virulence in Leishmania amazonensis. PLoS Negl Trop Dis 9: e0003804.

White, C., X. Yuan, P.J. Schmidt, E. Bresciani, T.K. Samuel, D. Campagna, C. Hall, K. Bishop, M.L. Calicchio, A. Lapierre, D.M. Ward, P. Liu, M.D. Fleming, and I. Hamza. (2013). HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17: 261-270.

Yuan, X., O. Protchenko, C.C. Philpott, and I. Hamza. (2012). Topologically conserved residues direct heme transport in HRG-1-related proteins. J. Biol. Chem. 287: 4914-4924.


TC#NameOrganismal TypeExample

The endosomal/lysosomal heme transporter, HRG-1 (SLC48.1) (Yuan et al., 2012)


SLC48A1 of Homo sapiens


The worm heme transporter, HRG-1 (Yuan et al., 2012).


HRG1 of Caenorhabditis elegans (Q21642)


HRG-4 heme transporter (Rajagopal et al. 2008).


HRG-4 of Caenorhabditis elegans (Q20106)


Putative heme transporter (151aas; 4 TMSs)


Heme transporter of Branchiostoma floridae (C3Y137)


Heme transporter Hrg-6 (Heme-responsive gene 6 protein) (CeHRG-6)


Hrg-6 of Caenorhabditis elegans


HRG homologue


HRG homologue of Acanthamoeba castellanii


TC#NameOrganismal TypeExample

The LHR1 heme uptake transporter (Huynh et al. 2012).  In Leishmania amazonensis, LHR1 is essential for virulence (Miguel et al. 2013).  Transport depends on tyrosyl residues in the first three TMSs of the protein (Renberg et al. 2015).


LHR1 of Leishmania donovani (E9BH93)


Heme uptake transporter, LHR1 (171aas; 4 putative TMSs) (Huynh et al. 2012).  Tyrosyl residues essential for activity are also essential for virulence (Renberg et al. 2015).


LHR1 of Trypanosoma cruzi (Q4DHZ7)