SLC48A1 (HRG1) notes

No deep-research provider was available for this gene; these notes are a manual
literature review (Europe PMC search, PMIDs verified and cached with
ai-gene-review fetch-pmid).

Identity

• Human SLC48A1 / HRG1, UniProt Q6P1K1, 146 aa, four predicted TM helices
  (FT TRANSMEM 12-32, 40-60, 74-94, 110-130), C-terminal di-leucine motif 142-143.
  HRG family (InterPro IPR026218, Pfam PF16954, PANTHER PTHR31525:SF1, TCDB 2.A.110.1.1).
• Mouse ortholog Q9D8M3 (Slc48a1); C. elegans hrg-1 Q21642 (paralog hrg-4 at the
  plasma membrane).

Function: heme transporter of endolysosomal / phagolysosomal membranes

• Discovery in C. elegans (heme auxotroph); human and worm HRG-1 "bind and transport
  haem" PMID:18418376 (abstract only cached).
  Per White et al. citing it, worm and human HRG1 co-localize with LAMP1, Rab7 and Rab11
  in HEK293 cells PMID:23395172.
• Conserved transport residues: a TMD2 histidine is required for transport by human
  HRG-1 in a yeast hem1-deletion heme-uptake assay PMID:22174408.
• Macrophages / erythrophagocytosis (EP): Hrg1 recruited to phagolysosomal membranes
  during EP, not during latex bead phagocytosis PMID:23395172;
  knockdown attenuates Hmox1/Fpn1 induction PMID:23395172.
  Human missense variant P36L abolishes transport in yeast PMID:23395172.
• Knockout mice: Slc48a1-/- RES macrophages accumulate heme as hemozoin in enlarged
  LAMP1+ lysosomes PMID:31571584;
  PMID:34713217.
• Zebrafish: Hrg1a/Hrg1b double KO impairs kidney macrophage heme-iron recycling
  PMID:30248094.
• Oligodendrocytes: highest Slc48a1 expression in mature OLs; Hrg1 null mice show
  myelin defects; OLs import heme/ZnMP [PMID:39501820 (abstract) "OL Hrg1 encodes a functional heme transporter required for myelin integrity"].

Disputed / secondary: V-ATPase association (O'Connor lab)

• O'Callaghan et al. 2010 PMID:19875448
  found HRG-1 in endosomes but not lysosomes and at the plasma membrane after nutrient
  withdrawal PMID:19875448.
  They also report the C-terminus to be extracellular/luminal, which conflicts with the
  Hamza lab topology (cytoplasmic C-terminus used as antibody epitope in PMID:23395172).
• Fogarty et al. 2014 PMID:24141772 (abstract only): plasma membrane HRG-1 with V-ATPase in
  invasive cancer cells.
• Treated as non-core; no GO annotation currently derived from these papers. Not proposed
  as NEW (V-ATPase regulator role not independently replicated).

Annotation decisions (summary)

• heme transmembrane transporter activity: ACCEPT (core).
• heme transport (all 4 rows): MODIFY to heme transmembrane transport GO:0035351 and,
  where supported, heme export from vacuole to cytoplasm GO:0140357 (lysosome lumen ->
  cytosol, matches topology and knockout phenotype).
• heme binding: KEEP_AS_NON_CORE (substrate binding, IDA in PMID:18418376).
• lysosomal membrane / endosome membrane: ACCEPT; lysosome (root organelle) ACCEPT.
• plasma membrane: KEEP_AS_NON_CORE (minor pool; worm HRG-4 is the plasma membrane paralog).
• phagocytic vesicle membrane: MODIFY -> phagolysosome membrane GO:0061474.
• protein binding x7 (HuRI/Y2H): REMOVE (uninformative).