Heme-induced iron-recycling macrophage differentiation

Macrophages that engulf aged or damaged red blood cells digest them in the phagolysosome and release heme. The heme transporter HRG1 carries heme out of the phagolysosome into the cytosol. Heme then switches on a differentiation programme. The transcriptional repressor BACH1 normally keeps the gene for the transcription factor SPI-C silent. Heme binds BACH1 through its cysteine-proline motifs and triggers its proteasomal degradation, which de-represses Spic. SPI-C drives monocytes to become iron-recycling macrophages: splenic red pulp macrophages and VCAM1-positive bone marrow macrophages. The same heme signal also de-represses the iron-recycling enzymes and transporters these cells use, heme oxygenase 1 and ferroportin.

MODULE:heme_induced_iron_recycling_macrophage_differentiationDRAFTABSTRACTDevelopmental Processmodules/heme_induced_iron_recycling_macrophage_differentiation.yaml
macrophage differentiationGO:0030225
PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
The authors' summary of the programme in vivo.
Bach1 inhibition at sites of erythrophagocytosis controls RPM and BMM development through derepression of Spic.
PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
The signal is heme itself, not a heme breakdown product.
Bilirubin and biliverdin failed to induce SPIC-EGFP in Spicigfp/igfp BMDM

Boundary: this module starts with heme in the phagolysosome of a macrophage that has engulfed an erythrocyte, and ends with a differentiated iron-recycling macrophage that exports iron. Engulfment of the erythrocyte and its digestion belong to the phagocytosis modules. The programme is defined by heme, not by phagocytosis. Heme released by haemolysis induces Spic in the same way. Engulfed erythrocytes are the main physiological source of heme for these cells. GO has no term for red pulp macrophage differentiation. The module concept is GO:0030225 macrophage differentiation, and "splenic red pulp macrophage differentiation" (is_a GO:0030225, cell type CL:0000874) has been proposed to the GO editors in go-ontology#32748. The two arms are supported by separate papers in different cells. HRG1 work is in bone-marrow-derived macrophages and spleen and liver macrophages without red pulp markers; the BACH1/SPIC work is in bone-marrow-derived macrophages, monocytes and chimeric mice. The link between them, phagolysosomal heme reaching BACH1, is inferred. Taxon scope: the programme is shown only in mouse. An OpenScientist phylogenetic profile (file:human/SPIC/SPIC-hypotheses/spic-bach1-cooccurrence/openscientist.md) found SPIC orthologs from cartilaginous fish through all bony vertebrates but not in cyclostomes or invertebrates, and found the BACH1 C-terminal cysteine-proline motif conserved in every curated bony-vertebrate BACH1 checked. No lineage has SPIC without BACH1. The parts of the switch therefore co-occur across jawed vertebrates, but whether the switch operates outside mammals is untested. HRG1 is conserved more widely across animals (C. elegans hrg-1 imports heme), so the heme-export step is broader than the differentiation programme. A second profile (file:human/SLC48A1/SLC48A1-hypotheses/hrg1-protist-distribution/openscientist.md) found the HRG1 family almost only in animals and choanoflagellates, with one ortholog in Acanthamoeba and none in Dictyostelium.

5Nodes
4Parts
0Variant Sets
0Variants
5Annotons
6Connections

Derived QC

Recommended-field compliance

60.0% recommended fields populated
  • references[0] · findings (0/1)
  • references[1] · findings (0/1)
  • references[2] · findings (0/1)
  • knowledge_gaps[0].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:heme_induced_iron_recycling_macrophage_differentiation deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 11 evidence or coverage gap(s) (16 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
hrg1_heme_transporter Slc48a1 (mouse)
UniProtKB:Q9D8M3
Family Representative 		heme transmembrane transporter activity
GO:0015232 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
hrg1_heme_transporter SLC48A1 (human)
UniProtKB:Q6P1K1
Family Representative 		heme transmembrane transporter activity
GO:0015232 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hrg1_heme_transporter hrg-1 (C. elegans)
UniProtKB:Q21642
Family Representative 		heme transmembrane transporter activity
GO:0015232 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bach1_repressor Bach1 (mouse)
UniProtKB:P97302
Family Representative 		DNA-binding transcription repressor activity, RNA polymerase II-specific
GO:0001227 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bach1_repressor BACH1 (human)
UniProtKB:O14867
Family Representative 		DNA-binding transcription repressor activity, RNA polymerase II-specific
GO:0001227 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
spic_tf Spic (mouse)
UniProtKB:Q6P3D7
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
spic_tf SPIC (human)
UniProtKB:Q8N5J4
Family Representative 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
hmox1_enzyme HMOX1 (human)
UniProtKB:P09601
Family Representative 		heme oxygenase (decyclizing) activity
GO:0004392 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmox1_enzyme Hmox1 (mouse)
UniProtKB:P14901
Family Representative 		heme oxygenase (decyclizing) activity
GO:0004392 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ferroportin_exporter SLC40A1 (human)
UniProtKB:Q9NP59
Family Representative 		iron ion transmembrane transporter activity
GO:0005381 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ferroportin_exporter Slc40a1 (mouse)
UniProtKB:Q9JHI9
Family Representative 		iron ion transmembrane transporter activity
GO:0005381 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
hrg1_heme_transporter HRG1 heme transporter
PANTHER:PTHR31525:SF1
Family 		heme transmembrane transporter activity
GO:0015232 		Family Supported
Family review supports GO:0015232 FAMILY_WIDE. The heme_induced_iron_recycling_macrophage_differentiation module uses this activity, at SF1. It is shown for SF1 (worm HRG-1, human HRG1, both zebrafish paralogs, and mouse in vivo) and for SF3 (worm HRG-4). It is safe family-wide. HRG-5 and HRG-6 are untested but have no known loss.
bach1_repressor BACH1
PANTHER:PTHR46105:SF1
Family 		DNA-binding transcription repressor activity, RNA polymerase II-specific
GO:0001227 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR46105:SF1.
spic_tf SPI-C
PANTHER:PTHR11849:SF17
Family 		DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0001228 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11849:SF17.
hmox1_enzyme heme oxygenase 1
PANTHER:PTHR10720:SF1
Family 		heme oxygenase (decyclizing) activity
GO:0004392 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10720:SF1.
ferroportin_exporter ferroportin
PANTHER:PTHR11660:SF47
Family 		iron ion transmembrane transporter activity
GO:0005381 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11660:SF47.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • bach1_repressor ⊣ spic_tf [closed]
    bach1_repressor is regulated by hrg1_heme_transporter: feedback loop closed

Gene-review completeness (5/11 grounded genes reviewed)

5 complete review(s) · 1 with deep research · 6 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
BACH1 O14867 ✓ ✓ ✗
HMOX1 P09601 ✓ ✓ ✗
Hmox1 (mouse) P14901 ✗ — —
Bach1 (mouse) P97302 ✗ — —
hrg-1 (C. elegans) Q21642 ✗ — —
Spic (mouse) Q6P3D7 ✗ — —
Slc48a1 (mouse) Q9D8M3 ✗ — —
Slc40a1 (mouse) Q9JHI9 ✗ — —
SLC40A1 Q9NP59 ✓ ✓ ✓
SLC48A1 Q6P1K1 ✓ ✓ ✗
SPIC Q8N5J4 ✓ ✓ ✗

Details

Context
MammaliaNCBITaxon:40674
splenic red pulp macrophageCL:0000874
Heme-induced iron-recycling macrophage differentiationDevelopmental Processheme_induced_iron_recycling_macrophage_differentiation
macrophage differentiationGO:0030225
Context
MammaliaNCBITaxon:40674
splenic red pulp macrophageCL:0000874

Connections

hrg1_heme_transporter -> bach1_repressor Provides Input For
Heme exported from the phagolysosome is the input that inactivates BACH1. This link is inferred; the two steps were studied separately.
hrg1_heme_transporter -> hmox1_enzyme Provides Input For
Heme oxygenase faces the cytosol, so it needs exported heme.
bach1_repressor -> spic_tf Negatively Regulates
BACH1 represses Spic until heme triggers its degradation.
bach1_repressor -> hmox1_enzyme Negatively Regulates
bach1_repressor -> ferroportin_exporter Negatively Regulates
hmox1_enzyme -> ferroportin_exporter Provides Input For
Iron released from heme is exported by ferroportin.
Part 1: heme export from the phagolysosome
HRG1 exports heme from the phagolysosomeTransport Stepphagolysosomal_heme_export

Haemoglobin is digested in the phagolysosome and its heme is released there. Heme oxygenase faces the cytosol, so heme must cross the phagolysosomal membrane. HRG1 is recruited to that membrane during erythrophagocytosis and moves heme into the cytosol.

heme export from vacuole to cytoplasmGO:0140357

Annotons

HRG1 heme transporter
hrg1_heme_transporter
Participant: Family: HRG1 heme transporter
Family:
HRG1 heme transporterPANTHER:PTHR31525:SF1
Representative Members: Slc48a1 (mouse)UniProtKB:Q9D8M3 SLC48A1 (human)UniProtKB:Q6P1K1 hrg-1 (C. elegans)UniProtKB:Q21642

Function

heme transmembrane transporter activityGO:0015232

Locations

phagolysosome membraneGO:0061474

Delivers heme from engulfed erythrocytes to the cytosol. Its knockdown blunts induction of heme-responsive genes during erythrophagocytosis.

PMID:23395172
HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis.
HRG1 moves to the phagolysosome only when red cells, not beads, are engulfed.
Hrg1 was recruited to the phagolysosomal membranes specifically during phagocytosis of RBCs but not latex beads
PMID:23395172
HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis.
The loss-of-function readout is indirect, through heme-responsive transcripts.
Hrg1 knockdown resulted in a significant attenuation of Hmox1 and Fpn1 mRNA induction during EP
Part 2: heme sensing
Heme-triggered BACH1 degradation de-represses SpicRegulatory Stepbach1_derepression

BACH1 represses Spic. Heme binds BACH1 through its C-terminal cysteine-proline motifs and triggers its proteasomal degradation. A BACH1 mutant without these motifs resists degradation and blocks Spic induction completely.

Annotons

BACH1 heme-sensing repressor
bach1_repressor
Participant: Family: BACH1
Family:
BACH1PANTHER:PTHR46105:SF1
Representative Members: Bach1 (mouse)UniProtKB:P97302 BACH1 (human)UniProtKB:O14867

Function

DNA-binding transcription repressor activity, RNA polymerase II-specificGO:0001227

Locations

nucleusGO:0005634

The heme sensor of the programme. Bach1-/- macrophages express Spic without heme, and a degradation-resistant mutant blocks induction. Whether BACH1 binds the Spic locus directly is not known.

PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
BACH1 represses Spic and heme relieves the repression.
These results demonstrate that Bach1 is a transcriptional repressor of Spic that is inhibited by heme.
PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
The cysteine-proline motifs are required for heme to induce Spic.
This demonstrates the requirement of heme-BACH1 interactions via CP motifs for heme-mediated Spic expression.
Part 3: lineage transcription factor
SPI-C drives iron-recycling macrophage differentiationDevelopmental Processspic_differentiation

De-repressed SPI-C drives monocytes to become red pulp macrophages and VCAM1-positive bone marrow macrophages. Spic-/- mice lack both.

Annotons

SPI-C transcription factor
spic_tf
Participant: Family: SPI-C
Family:
SPI-CPANTHER:PTHR11849:SF17
Representative Members: Spic (mouse)UniProtKB:Q6P3D7 SPIC (human)UniProtKB:Q8N5J4

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Processes

macrophage differentiationGO:0030225

Locations

nucleusGO:0005634

Lineage factor of iron-recycling macrophages, induced by heme.

PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
SPI-C is required for red pulp macrophages (earlier work) and for VCAM1-positive bone marrow macrophages (this paper).
mice were found to be deficient in F4/80hi VCAM1hi BMM in addition to the previously reported loss of RPM
Part 4: iron-recycling outputs (optional)
Heme catabolism and iron exportBiological Processiron_recycling_outputs

Heme also de-represses, through BACH1, the genes for heme oxygenase 1 and ferroportin. HMOX1 breaks heme down to release iron, and ferroportin exports the iron. These are the work the differentiated macrophage does, and the same derepression step controls them.

Annotons

Heme oxygenase 1
hmox1_enzyme
Participant: Family: heme oxygenase 1
Family:
heme oxygenase 1PANTHER:PTHR10720:SF1
Representative Members: HMOX1 (human)UniProtKB:P09601 Hmox1 (mouse)UniProtKB:P14901

Function

heme oxygenase (decyclizing) activityGO:0004392

Processes

heme catabolic processGO:0042167

Releases iron from heme in the cytosol. Its gene is de-repressed by heme through BACH1.

file:genes/human/HMOX1/HMOX1-ai-review.yaml
HMOX1 gene review
The HMOX1 review covers its heme oxygenase activity.
Ferroportin iron exporter
ferroportin_exporter
Participant: Family: ferroportin
Family:
ferroportinPANTHER:PTHR11660:SF47
Representative Members: SLC40A1 (human)UniProtKB:Q9NP59 Slc40a1 (mouse)UniProtKB:Q9JHI9

Function

iron ion transmembrane transporter activityGO:0005381

Processes

iron ion export across plasma membraneGO:1903988

Locations

plasma membraneGO:0005886

Exports the recycled iron. Its gene is de-repressed by heme through BACH1.

PMID:24630724
Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages.
Heme de-represses Spic, Ho1 and Slc40a1 through BACH1.
derepression of Spic, Ho1, and SLC40A1 by heme was dependent on Bach1