IgG receptor FcRn large subunit p51 (FCGRT) is a single-pass type I membrane glycoprotein that associates non-covalently with beta-2-microglobulin (B2M) to form the heterodimeric neonatal Fc receptor (FcRn). Structurally homologous to major histocompatibility complex (MHC) class I heavy chains, FCGRT possesses extracellular alpha-1, alpha-2, and Ig-like C1-type alpha-3 domains, but its alpha-1/alpha-2 groove is occluded and does not bind antigenic peptides. Instead, FcRn cycles between the endosome membrane and the plasma membrane, capturing the Fc region of monomeric immunoglobulin G (IgG) and serum albumin at acidic endosomal pH (pH 5.5-6.0) and releasing them at neutral extracellular pH (pH 7.4). Through this pH-dependent ligand sorting mechanism, FCGRT mediates transcellular maternal-fetal and intestinal IgG transport (transcytosis) as well as continuous endosomal recycling of circulating IgG and albumin in endothelial and hematopoietic cells to maintain their serum half-lives. During microbial infection, the FCGRT subunit of FcRn is hijacked in acidic endosomes as the cellular uncoating receptor for major Enterovirus B serotypes.
Definition: The directed transcellular transport of serum albumin across a polarized cell from one cellular surface to another via endocytic uptake, pH-dependent sorting in endosomes, and exocytic release.
Justification: GO currently provides GO:0002416 (IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor) and parent GO:0045056 (transcytosis), which cannot be added as a NEW annotation on FCGRT because FCGRT already carries its descendant GO:0002416. A specific sibling term for albumin transcytosis is needed to represent FcRn-mediated transcellular albumin transport (PMID:28330995) without duplicating ancestor GO:0045056.
Parent term: transcytosis
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002416 IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor | NAS PMID:7964511 A major histocompatibility complex class I-like Fc receptor ... | ACCEPT | Summary: Core biological process of FCGRT in mediating transcellular transport of maternal IgG across polarized epithelial barriers. Reason: Story et al. (1994) cloned human FCGRT (hFcRn) from placenta, demonstrated its pH-dependent binding to IgG at acidic pH, and established its conservation with rodent neonatal intestinal FcRn that mediates epithelial IgG transcytosis. Subsequent functional studies confirmed that human FcRn mediates bidirectional IgG transcytosis across placental syncytiotrophoblasts and intestinal epithelial cells. Supporting Evidence: PMID:7964511 Like rat and mouse FcRn, hFcRn binds IgG preferentially at low pH, which may imply that IgG binds hFcRn in an acidic intracellular compartment during transport across the placenta. file:genes/human/FCGRT/FCGRT-uniprot.txt The resultant FcRn-IgG complexes are transcytosed across the intestinal epithelium and IgG is released from FcRn into blood or tissue fluids. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a high-throughput yeast two-hybrid screen (with UPK2) is uninformative. Reason: Bare protein binding (GO:0005515) from the proteome-wide HuRI yeast two-hybrid screen (PMID:32296183) with uroplakin-2 (UPK2, O00526) does not specify a meaningful molecular function for FCGRT; its specific physiological interactions are captured by GO:0019864 (IgG binding) and GO:0030881 (beta-2-microglobulin binding). Removing this generic term does not dispute the reported binary assay hit. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a high-throughput yeast two-hybrid screen (with PMP22) is uninformative. Reason: Bare protein binding (GO:0005515) from the proteome-wide HuRI yeast two-hybrid screen (PMID:32296183) with peripheral myelin protein 22 (PMP22, Q01453) does not specify a meaningful molecular function for FCGRT; its specific physiological interactions are captured by GO:0019864 (IgG binding) and GO:0030881 (beta-2-microglobulin binding). Removing this generic term does not dispute the reported binary assay hit. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a high-throughput yeast two-hybrid screen (with CLDN19) is uninformative. Reason: Bare protein binding (GO:0005515) from the proteome-wide HuRI yeast two-hybrid screen (PMID:32296183) with claudin-19 (CLDN19, Q8N6F1-2) does not specify a meaningful molecular function for FCGRT; its specific physiological interactions are captured by GO:0019864 (IgG binding) and GO:0030881 (beta-2-microglobulin binding). Removing this generic term does not dispute the reported binary assay hit. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a high-throughput yeast two-hybrid screen (with FAM3C) is uninformative. Reason: Bare protein binding (GO:0005515) from the proteome-wide HuRI yeast two-hybrid screen (PMID:32296183) with protein FAM3C (Q92520) does not specify a meaningful molecular function for FCGRT; its specific physiological interactions are captured by GO:0019864 (IgG binding) and GO:0030881 (beta-2-microglobulin binding). Removing this generic term does not dispute the reported binary assay hit. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from a high-throughput yeast two-hybrid screen (with NINJ2) is uninformative. Reason: Bare protein binding (GO:0005515) from the proteome-wide HuRI yeast two-hybrid screen (PMID:32296183) with ninjurin-2 (NINJ2, Q9NZG7) does not specify a meaningful molecular function for FCGRT; its specific physiological interactions are captured by GO:0019864 (IgG binding) and GO:0030881 (beta-2-microglobulin binding). Removing this generic term does not dispute the reported binary assay hit. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | MODIFY | Summary: FCGRT is an integral single-pass type I membrane receptor rather than a soluble secreted extracellular protein; refine to external side of plasma membrane and endosome membrane. Reason: The ancestral MHC class I-related node PANTHER:PTN002703355 includes secreted or shed family members such as zinc-alpha-2-glycoprotein (AZGP1, P25311) and soluble HLA-G isoforms (P17693). However, human FCGRT is a single-pass type I transmembrane protein (residues 298-321) that is not secreted into the soluble extracellular space; its ectodomain faces the extracellular space at the cell surface (GO:0009897, external side of plasma membrane) and the lumen of acidic endosomes (GO:0010008, endosome membrane), both of which are already annotated on this gene. Proposed replacements: external side of plasma membrane endosome membrane Supporting Evidence: file:genes/human/FCGRT/FCGRT-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13599}; Single-pass type I membrane protein {ECO:0000255}. Endosome membrane {ECO:0000269|PubMed:31104841}. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: FCGRT localizes to the plasma membrane during exocytic release of recycled or transcytosed IgG and albumin. Reason: FCGRT is a single-pass type I membrane protein that traffics between acidic endosomal compartments and the plasma membrane, where neutral extracellular pH triggers release of bound IgG and albumin. Immunofluorescence and cell-surface assays confirm its presence at the plasma membrane as well as in endosomes. Supporting Evidence: PMID:31104841 FcRn is expressed both on the cell surface and in the cytoplasm. file:genes/human/FCGRT/FCGRT-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13599}; Single-pass type I membrane protein {ECO:0000255}. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Orthology to rat Fcgrt and direct human cell-surface detection support plasma membrane localization. Reason: Like its rat ortholog Fcgrt (UniProtKB:P13599), human FCGRT localizes to the plasma membrane and recycles between the cell surface and endosomal membranes during IgG transcytosis and salvage. Supporting Evidence: PMID:31104841 FcRn is expressed both on the cell surface and in the cytoplasm. file:genes/human/FCGRT/FCGRT-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13599}; Single-pass type I membrane protein {ECO:0000255}. |
| GO:0006955 immune response | IBA GO_REF:0000033 | MODIFY | Summary: Broad immune response annotation from the MHC class I-like PANTHER node is better represented by FcRn-mediated IgG transcytosis. Reason: PANTHER:PTN002703355 encompasses classical MHC class I alpha chains (HLA-A, HLA-B, HLA-E, HLA-G), MICA, and ULBPs, which mediate antigen presentation and NK-cell activation. Unlike those paralogous lineages, FCGRT has an occluded peptide groove and contributes to humoral immunity specifically through pH-dependent epithelial IgG transcytosis and endosomal IgG salvage, which is more precisely captured by GO:0002416 (IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor), already present on this gene. Proposed replacements: IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor Supporting Evidence: file:genes/human/FCGRT/FCGRT-uniprot.txt Cell surface receptor that transfers passive humoral immunity from the mother to the newborn. |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The ligand-binding alpha-1/alpha-2/alpha-3 ectodomain of FCGRT projects to the external side of the plasma membrane. Reason: FCGRT is a single-pass type I membrane glycoprotein whose extracellular topological domain (residues 24-297) and associated B2M subunit face the extracellular space when at the plasma membrane (and topologically equivalent endosomal lumen upon internalization), where it binds or releases maternal/circulating IgG. Supporting Evidence: file:genes/human/FCGRT/FCGRT-uniprot.txt IgG in the milk is bound at the apical surface of the intestinal epithelium. |
| GO:0010008 endosome membrane | EXP PMID:31104841 Human Neonatal Fc Receptor Is the Cellular Uncoating Recepto... | ACCEPT | Summary: Primary intracellular site where FCGRT binds IgG and albumin and mediates enterovirus B uncoating at acidic pH. Reason: Confocal microscopy and functional assays in PMID:31104841, together with established FcRn trafficking biology, show that FCGRT predominantly resides on the endosome membrane where acidic pH (pH 5.5-6.0) enables pH-dependent IgG/albumin binding and triggers Enterovirus B pocket-factor release. Supporting Evidence: PMID:31104841 Consistently, CD55 was mainly localized on the cell surface, whereas FcRn displayed substantial expression within the cytoplasm, presumably on the endosome membrane |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping accurately captures endosome membrane localization of FCGRT. Reason: Consistent with the experimental annotation from PMID:31104841, FCGRT localizes to the endosome membrane where pH-dependent IgG and albumin sorting occurs. Supporting Evidence: file:genes/human/FCGRT/FCGRT-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13599}; Single-pass type I membrane protein {ECO:0000255}. Endosome membrane {ECO:0000269|PubMed:31104841}. |
| GO:0016020 membrane | IEA GO_REF:0000117 | MODIFY | Summary: True but overly general membrane annotation; refine to endosome membrane and plasma membrane. Reason: FCGRT is an integral single-pass type I membrane protein, but its specific membrane compartmentsβthe endosome membrane (GO:0010008) and plasma membrane (GO:0005886)βare well established and already asserted in this review. Proposed replacements: endosome membrane plasma membrane Supporting Evidence: file:genes/human/FCGRT/FCGRT-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P13599}; Single-pass type I membrane protein {ECO:0000255}. Endosome membrane {ECO:0000269|PubMed:31104841}. |
| GO:0019864 IgG binding | IDA PMID:7964511 A major histocompatibility complex class I-like Fc receptor ... | ACCEPT | Summary: Core molecular function of FCGRT in binding the Fc region of monomeric IgG at acidic pH. Reason: Story et al. (1994) directly demonstrated that human FCGRT (hFcRn) binds IgG preferentially at acidic pH (pH 6.0) and releases it at neutral pH (pH 7.5), which is the foundational molecular activity driving both epithelial IgG transcytosis and endosomal IgG salvage. Supporting Evidence: PMID:7964511 Like rat and mouse FcRn, hFcRn binds IgG preferentially at low pH, which may imply that IgG binds hFcRn in an acidic intracellular compartment during transport across the placenta. |
| GO:0030881 beta-2-microglobulin binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core structural and functional heterodimerization of FCGRT heavy chain with beta-2-microglobulin. Reason: FCGRT obligately pairs non-covalently with beta-2-microglobulin (B2M) to form the mature heterodimeric FcRn complex; co-expression, purification, and X-ray/cryo-EM structures confirm direct B2M binding conserved across mammalian FcRn orthologs. Supporting Evidence: PMID:31104841 FcRn is an MHC class I-like protein consisting of a heavy Ξ± chain encoded by the FCGRT gene, and a light Ξ²2-microglubulin (Ξ²2 m) chain encoded by the B2M gene. file:genes/human/FCGRT/FCGRT-uniprot.txt SUBUNIT: FcRn complex consists of two subunits: p51, and p14 which is equivalent to beta-2-microglobulin. It forms an MHC class I-like heterodimer (By similarity). |
| GO:0030881 beta-2-microglobulin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved direct binding of FCGRT to beta-2-microglobulin to form the heterodimeric FcRn receptor. Reason: Orthology transfer from rat Fcgrt (P13599) and direct biochemical/structural characterization of human FcRn confirm that FCGRT directly binds beta-2-microglobulin (B2M) to form the functional MHC class I-like heterodimer. Supporting Evidence: PMID:31104841 FcRn is an MHC class I-like protein consisting of a heavy Ξ± chain encoded by the FCGRT gene, and a light Ξ²2-microglubulin (Ξ²2 m) chain encoded by the B2M gene. |
| GO:0042605 peptide antigen binding | ISS NOT GO_REF:0000024 | ACCEPT | Summary: Correct negative annotation; despite MHC class I structural homology, the FCGRT alpha-1/alpha-2 groove is occluded and cannot bind antigenic peptides. Reason: Although FCGRT is an MHC class I-like heavy chain, X-ray crystal structures of both rat (P13599) and human (P55899) FcRn demonstrate that the counterpart to the MHC class I peptide-binding groove is closed and occluded by side-chain interactions bridging the alpha-1 and alpha-2 helices, precluding peptide antigen binding. Supporting Evidence: PMID:10933786 FcRn is related to class I MHC proteins but lacks a functional peptide binding groove. |
| GO:0038024 cargo receptor activity | IDA PMID:24469444 Structural insights into neonatal Fc receptor-based recyclin... | NEW | Summary: Proposed NEW annotation for pH-dependent endocytic cargo receptor activity binding serum albumin and monomeric IgG at non-overlapping sites in acidic endosomes. Reason: X-ray crystal structures and functional studies demonstrate that human FCGRT (paired with B2M) functions as a dual-ligand endocytic cargo receptor that binds both human serum albumin and monomeric IgG at non-overlapping sites in acidic endosomes (pH 5.5-6.0) and releases them at neutral extracellular pH (pH 7.4). Because no specific GO molecular function term exists for albumin receptor activity, GO:0038024 (cargo receptor activity) captures this receptor activity. Supporting Evidence: PMID:24469444 We report the three-dimensional structure of human neonatal Fc receptor (FcRn) bound concurrently to its two known ligands. More particularly, we solved the crystal structure of the complex between human FcRn, wild-type human serum albumin (HSA), and a human Fc engineered for improved pharmacokinetics properties (Fc-YTE). file:genes/human/FCGRT/FCGRT-uniprot.txt In addition of IgG, regulates homeostasis of the other most abundant circulating protein albumin/ALB (PubMed:24469444, PubMed:28330995). |
| GO:0001618 virus receptor activity | IDA PMID:31104841 Human Neonatal Fc Receptor Is the Cellular Uncoating Recepto... | NEW | Summary: Proposed NEW annotation for FCGRT acting as the endosomal uncoating receptor for major Enterovirus B serotypes during microbial infection. Reason: Cryo-EM structures and functional entry assays in PMID:31104841 show that during Enterovirus B (EV-B) infection, human FcRn binds the viral capsid canyon directly through its FCGRT subunit and mediates acid-triggered viral uncoating in endosomes. Supporting Evidence: PMID:31104841 Here, we found that human neonatal Fc receptor (FcRn) is the uncoating receptor for major EV-B. FcRn binds to the virus particles in the "canyon" through its FCGRT subunit. file:genes/human/FCGRT/FCGRT-uniprot.txt FUNCTION: (Microbial infection) Acts as an uncoating receptor for a panel of echoviruses including Echovirus 5, 6, 7, 9, 11, 13, 25 and 29. |
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Download this section (compressed HTML)Q: How do tissue-specific differences in endosomal pH regulation and cytoplasmic tail phosphorylation (such as Ser334) modulate the balance between FcRn-mediated recycling versus bidirectional transcytosis of IgG and albumin across endothelial, placental, and hepatic cells?
Q: Does the non-overlapping pH-dependent binding of serum albumin (ALB) and monomeric IgG to the FCGRT-B2M heterodimer exhibit cooperative allostery during endosomal sorting in vivo?
Experiment: Perform live-cell quantitative fluorescence lifetime and pH-ratiometric imaging of endogenous human FCGRT-B2M heterodimers simultaneously bound to fluorescently labeled monomeric IgG and serum albumin in polarized human syncytiotrophoblast and hepatic organoids to determine whether dual-ligand occupancy alters sorting kinetics between recycling endosomes and transcytotic vesicles.
Hypothesis: Simultaneous occupancy of the non-overlapping IgG and albumin binding sites on FCGRT stabilizes the heterodimer in sorting tubules without competitive displacement, but phosphorylation of Ser334 in the cytoplasmic tail selectively biases polarized sorting toward apical-to-basolateral transcytosis in epithelial barriers.
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