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PMID:23395172

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Citation

White, C, Yuan, X, Schmidt, PJ, Bresciani, E, Samuel, TK, Campagna, D, Hall, C, Bishop, K, Calicchio, ML, Lapierre, A, Ward, DM, Liu, P, Fleming, MD and Hamza, I (2013) HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab. 17:261-70

Abstract

Adult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 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.

Links

PubMed PMC3582031 Online version:10.1016/j.cmet.2013.01.005

Keywords

Animals; Biological Transport; Erythrocytes/cytology; Erythrocytes/metabolism; Genes, Reporter; HEK293 Cells; Heme/metabolism; Hemeproteins/metabolism; Hemolysis; Humans; Intracellular Membranes/metabolism; Iron/metabolism; Macrophages/cytology; Macrophages/metabolism; Mice; Mononuclear Phagocyte System/cytology; Mutation, Missense/genetics; Phagocytosis; Phagosomes/metabolism; Polymorphism, Single Nucleotide/genetics; RNA, Messenger/genetics; RNA, Messenger/metabolism; Zebrafish

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LAMP1

located_in

GO:0061474: phagolysosome membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000235)

Seeded From UniProt

complete

MOUSE:HMOX1

acts_upstream_of_or_within

GO:0034395: regulation of transcription from RNA polymerase II promoter in response to iron

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HEMH

acts_upstream_of_or_within

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG1

acts_upstream_of_or_within

GO:0015886: heme transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LAMP3

located_in

GO:0005764: lysosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HRG

acts_upstream_of_or_within

GO:0034395: regulation of transcription from RNA polymerase II promoter in response to iron

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HRG

located_in

GO:0036019: endolysosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HRG

acts_upstream_of_or_within

GO:0015886: heme transport

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q6P1K1

P

Seeded From UniProt

complete

MOUSE:HRG

acts_upstream_of_or_within

GO:0015886: heme transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HRG

acts_upstream_of_or_within

GO:0014070: response to organic cyclic compound

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HRG

located_in

GO:0061474: phagolysosome membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HRG

located_in

GO:0031982: vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HRG

acts_upstream_of_or_within

GO:0097037: heme export

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:S40A1

acts_upstream_of_or_within

GO:0034395: regulation of transcription from RNA polymerase II promoter in response to iron

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LAMP1

part_of

GO:0061474: phagolysosome membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000235)

Seeded From UniProt

complete

Notes

See also

References

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