HRG1 Is Essential for Heme Transport from the Phagolysosome of Macrophages during Erythrophagocytosis

Abstract

Adult humans have about 25 trillion red blood cells (RBCs) and each second we recycle about five million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show 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 causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism.

Iron homeostasis: An anthropocentric perspective

“…These processes may occur in different cellular compartments, with hemoglobin proteolysis in the phagolysosome and heme degradation in the cytosol (24), necessitating the export of heme from the phagolysosome prior to heme catabolism. The protein heme-responsive gene-1 (HRG-1) is expressed in macrophages and exports heme from the phagolysosome into the cytosol (25). To date, mammalian models lacking HRG-1 have not been reported, but suppression of HRG-1 in developing zebrafish results in developmental and erythropoietic defects (26).…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…In the early endosome, the CD163 receptor is recycled to the cell surface, while the globin chain of Hb is degraded in the late endosome. Heme from Hb is then transported from the lumen of the phagolysosome to microsomal HO-1 via the lysosomal transporters HCP-1 or HRG-1 where it is degraded to iron, CO, and biliverdin (150,184). CO is an anti-inflammatory and cytoprotective gas (129,160).…”

Regulation of heme biosynthesis and transport in metazoa

“…As discussed above, C. elegans HRG-1 transports heme from the endosomal-lysosomal organelles to the cytosol within the intestinal cells [70]. Similarly, mammalian HRG1 transports heme from the phagolysosomes to the cytosol of the reticuloendothelial macrophages [75]. During erythrophagocytosis, macrophage phagolysosomes are responsible for breaking down ingested red blood cells to release heme.…”

“…Knockdown of hrg1 in zebrafish resulted in hypochromic anemia [70]. The expression of HRG1 in reticuloendothelial macrophages is up-regulated by both erythrophagocytosis and heme [75]. Thus, vertebrate HRG1 plays a critical role in recycling heme and heme iron from the senescent red blood cells [75].…”

“…HRG1 specifically localizes to the phagolysosomal membranes during erythrophagocytosis. Silencing of HRG1 significantly reduced the heme levels in the cytosol of bone marrow-derive macrophages [75]. Knockdown of hrg1 in zebrafish resulted in hypochromic anemia [70].…”