FCGRT Human
Description
Physiological Roles
FCGRT mediates IgG recycling and transcytosis, extending its half-life and regulating albumin.
IgG Recycling Mechanism
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Endosomal Binding: IgG internalized via pinocytosis binds FCGRT in acidic endosomes.
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Recycling: FCGRT-IgG complexes recycle to the cell surface, releasing IgG into circulation.
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Albumin Regulation: Similar recycling mechanism prevents lysosomal degradation of albumin .
| Protein | Half-Life | Role of FCGRT | Source |
|---|---|---|---|
| IgG | ~21 days | Prevents catabolism via pH-dependent recycling | |
| Albumin | ~19 days | Regulates turnover in endothelial cells |
Therapeutic Applications
FCGRT’s IgG recycling properties are leveraged to enhance drug persistence and target autoimmune diseases.
Half-Life Extension of Biologics
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Engineered IgG: Mutations (e.g., YTE, Abdeg) increase FCGRT binding affinity, extending half-lives. Examples include Ultomiris (ravulizumab) and Evusheld (tixagevimab/cilgavimab) .
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Albumin Variants: Modified albumin (e.g., Albutein) binds FCGRT, improving pharmacokinetics .
| Drug | Target | Mechanism | Source |
|---|---|---|---|
| Enbrel (etanercept) | TNF-α | TNF-binding Fc-linked soluble receptor | |
| Efgartigimod | FCGRT | Blocks IgG recycling (approved for myasthenia gravis) |
Pathological Roles
FCGRT is implicated in autoimmune diseases and cancer progression.
Autoimmune Diseases
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Pathogenic IgG: FCGRT prolongs the half-life of autoantibodies, exacerbating conditions like myasthenia gravis.
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Therapies: FCGRT inhibitors (e.g., rozanolixizumab, nipocalimab) disrupt IgG recycling, reducing disease severity .
Cancer
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Glioma Prognosis: High FCGRT expression correlates with shorter survival and increased immune cell infiltration (e.g., macrophages) .
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Mechanism: FCGRT knockdown in glioma cells reduces proliferation and migration, suggesting a role in tumor progression .
| Cancer Type | FCGRT Expression | Outcome | Source |
|---|---|---|---|
| Glioma | High | Poor prognosis, shorter survival | |
| Immune Microenvironment | Correlated with macrophage infiltration | Enhanced tumor immune evasion |
Genetic and Epigenetic Regulation
Polymorphisms and DNA methylation influence FCGRT expression.
Genetic Variants
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VNTR Polymorphisms: VNTR3 allele increases FCGRT transcription but does not significantly affect IgG transfer or therapeutic antibody clearance .
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Disease-Associated Variants: Limited publicly reported mutations (LOVD database lists 5 variants, no individual cases) .
| Variant | Effect | Source |
|---|---|---|
| VNTR3 | Higher transcriptional activity | |
| DNA Methylation | Reduced expression in liver/myocardium |
Experimental Models and Tools
Recombinant FCGRT proteins and tagged clones enable functional studies.
| Product | Application | Source |
|---|---|---|
| Recombinant FCGRT (51–160 aa) | SDS-PAGE, ELISA, Western blotting | |
| Tagged ORF Clones | Protein expression (Myc-DDK, GST tags) |
Tissue Distribution
FCGRT is expressed in diverse tissues, including immune and epithelial cells.
Product Specs
IgG receptor FcRn large subunit p51, FcRn, IgG Fc fragment receptor transporter alpha chain, Neonatal Fc receptor, Fcgrt, Fcrn.
HEK293 Cells.
FCGRT
AESHLSLLYH LTAVSSPAPG TPAFWVSGWL GPQQYLSYNS LRGEAEPCGA WVWENQVSWY WEKETTDLRI KEKLFLEAFK ALGGKGPYTL QGLLGCELGP DNTSVPTAKF ALNGEEFMNF DLKQGTWGGD WPEALAISQR WQQQDKAANK ELTFLLFSCP HRLREHLERG RGNLEWKEPP SMRLKARPSS PGFSVLTCSA FSFYPPELQL RFLRNGLAAG TGQGDFGPNS DGSFHASSSL TVKSGDEHHY CCIVQHAGLA QPLRVELESP AKSSHHHHHH.
B2M
IQRTPKIQVY SRHPAENGKS NFLNCYVSGF HPSDIEVDLL KNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQP KIVKWDRDM.
Q&A
Here’s a structured collection of research-focused FAQs on FCGRT (human Fc gamma receptor and transporter), incorporating experimental design, methodological insights, and data-driven analysis:
What are the primary functional roles of FCGRT in IgG homeostasis?
Methodological Answer:
FCGRT encodes the neonatal Fc receptor (FcRn), which regulates IgG homeostasis via pH-dependent binding. To study this:
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In vitro: Use polarized epithelial/endothelial cell lines (e.g., Caco-2, HSkMEC) to model FcRn-mediated IgG transcytosis .
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In vivo: Employ FcRn-humanized murine models (e.g., Tg32 strain) to assess IgG pharmacokinetics under competitive conditions .
Key Finding: FcRn extends IgG half-life by recycling antibodies via endosomal sorting, reducing lysosomal degradation .
How to validate FCGRT expression in human cell lines?
Experimental Design:
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RT-PCR: Amplify a 457-bp fragment of FCGRT mRNA (primers spanning exons 2–4) .
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Negative Controls: Include HL-60 cells (lack FCGRT expression) and omit reverse transcription to rule out genomic DNA contamination .
Validation Table:
| Cell Line | FCGRT mRNA Detected? | Functional FcRn Protein? |
|---|---|---|
| Caco-2 | Yes | Yes (pH-dependent binding) |
| THP-1 (PMA-differentiated) | Yes | Yes (enhanced post-differentiation) |
| HL-60 | No | No |
What transcriptional regulators control FCGRT expression in different tissues?
Mechanistic Approach:
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Electrophoretic Mobility Shift Assay (EMSA): Identify transcription factors (e.g., Sp1, AP-1, C/EBPβ) binding to the FCGRT promoter (-660/-233 region) .
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Site-Directed Mutagenesis: Disrupt putative binding sites (e.g., -497 C/EBPβ motif) to quantify promoter activity loss in luciferase assays .
Contradiction Note: While Sp1/AP-1 are critical in epithelial cells, C/EBPβ dominates in macrophages (THP-1), suggesting tissue-specific regulation .
How does DNA methylation influence FCGRT expression variability?
Epigenetic Analysis:
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Bisulfite Sequencing: Compare methylation at CpG sites in liver (high FcRn) vs. myocardium (low FcRn).
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Functional Correlation: Hypomethylation in the -1058 to -587 bp region correlates with 2.5-fold higher FCGRT mRNA in hepatic cells .
Why do FCGRT expression levels vary in cancer, and how to interpret clinical relevance?
Translational Workflow:
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IHC Staining: Score FCGRT expression in glioma biopsies (cytoplasmic/membrane localization) .
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Survival Analysis: High FCGRT correlates with shorter survival (HR = 6.41, P < 0.001) .
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Immune Context: FCGRT+ gliomas show CD68+ macrophage infiltration, suggesting FcRn-IgG immune complex interplay .
How to reconcile discrepancies in FcRn-blocking therapeutic outcomes?
Critical Analysis:
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Model Limitations: Murine Tg32 models lack endogenous human IgG competition, overestimating mAb half-life .
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Mitigation Strategy: Use CRISPR-engineered Tg32 mice with human IGHG1 Fc to mimic physiological IgG-FcRn competition .
Why do in vitro promoter studies conflict with in vivo FcRn expression patterns?
Hypothesis Testing:
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Chromatin Conformation Assays: Perform 3C or Hi-C to assess long-range chromatin interactions in primary tissues vs. cell lines.
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In Vivo Validation: Use conditional FCGRT knockout models to dissect enhancer regions missed in vitro .
Methodological Tools Table
Key Research Challenges
Product Science Overview
The Fc fragment of IgG receptor and transporter, also known as the neonatal Fc receptor (FcRn), is a crucial component in the immune system. It plays a significant role in the regulation and transport of immunoglobulin G (IgG) antibodies. This receptor is particularly important for maintaining the homeostasis of IgG and extending its half-life in the bloodstream.
FcRn is a transmembrane glycoprotein with structural homology to MHC class I proteins . It is composed of two subunits: the alpha chain (FCGRT) and beta-2-microglobulin (B2M), forming an MHC class I-like heterodimer . The Fc fragment of IgG binds to FcRn with high affinity at acidic pH (around pH 6) and releases at neutral pH (around pH 7.4) .
FcRn is widely expressed in endothelial and epithelial cells and plays a pivotal role in IgG homeostasis . It rescues IgG from degradation by binding to it in the acidic environment of endosomes and recycling it back to the cell surface, where it is released into the bloodstream at neutral pH . This process significantly extends the half-life of IgG, allowing it to persist in the circulation for an extended period.
One of the critical functions of FcRn is the transplacental transport of IgG from the mother to the fetus. During pregnancy, FcRn mediates the transfer of maternal IgG across the placenta, providing the fetus with passive immunity . This transfer is essential for protecting the newborn from infections during the early stages of life.
Recombinant human FcRn has been utilized in various therapeutic applications. By manipulating the Fc region of IgG, researchers have developed antibodies with altered binding properties to FcRn. These modifications can enhance or reduce the half-life of therapeutic antibodies, depending on the desired outcome . Additionally, FcRn-based therapies are being explored for their potential in treating autoimmune diseases and improving the efficacy of antibody-based drugs .
