Visualizing the Site and Dynamics of IgG Salvage by the MHC Class I-Related Receptor, FcRn

Ober, Raimund J.; Martinez, Cruz; Vaccaro, Carlos; Zhou, Jianuan; Ward, E. Sally

doi:10.4049/jimmunol.172.4.2021

Cited by 271 publications

(334 citation statements)

References 54 publications

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“…We have shown previously that human FcRn sorts bound IgG into a recycling pathway that overlaps with that taken by the transferrin receptor (32). This sorting occurs in early endosomes that, based on transferrin and dextran trafficking, can be defined as sorting endosomes.…”

Section: Resultsmentioning

confidence: 99%

“…The pH dependence of the IgG-FcRn interaction is such that binding is relatively strong at pH 6.0 but becomes negligible as near-neutral pH is approached (28)(29)(30)(31). Following uptake into cells, IgG can therefore bind to FcRn in slightly acidic sorting endosomes (32). FcRn subsequently transports bound IgG from the sorting endosomes to the plasma membrane, where cargo is released at near-neutral pH during exocytic events (10).…”

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confidence: 99%

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Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy

Prabhat

Gan

Chao

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The intracellular events on the recycling pathway that lead from sorting endosomes to exocytosis at the plasma membrane are central to cellular function. However, despite intensive study, these processes are poorly characterized in spatial and dynamic terms. The primary reason for this is that, to date, it has not been possible to visualize rapidly moving intracellular compartments in three dimensions in cells. Here, we use a recently developed imaging setup in which multiple planes can be simultaneously imaged within the cell in conjunction with visualization of the plasma membrane plane by using total internal reflection fluorescence microscopy. This has allowed us to track and characterize intracellular events on the recycling pathway that lead to exocytosis of the MHC Class I-related receptor, FcRn. We observe both direct delivery of tubular and vesicular transport containers (TCs) from sorting endosomes to exocytic sites at the plasma membrane, and indirect pathways in which TCs that are not in proximity to sorting endosomes undergo exocytosis. TCs can also interact with different sorting endosomes before exocytosis. Our data provide insight into the intracellular events that precede exocytic fusion.immunoglobulin G ͉ multifocal plane imaging ͉ neonatal Fc receptor ͉ sorting endosome ͉ total internal reflection

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy

Prabhat

Gan

Chao

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

142

150

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“…Therefore, the plasma concentration is not identical to but is an index for endosomal unbound IgG concentration (see Results and Discussion). FcRn-bound IgG is recycled to the plasma at a rate controlled by a fractional endosomal recycling rate (k rec ) whereas unbound IgG is degraded [25][26][27] at a rate controlled by a fractional endosomal degradation rate (k deg ). The distribution of IgG between the vascular and extravascular compartments was assumed to be FcRn-independent and is controlled by fractional intercompartmental distribution rates (k 12 and k 21 ).…”

Section: The Integrated Kinetic Modelmentioning

confidence: 99%

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

175

122

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The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.

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“…The neonatal Fc receptor (FcRn) serves to rescue the two most abundant soluble proteins in serum, IgG and albumin, from degradation, and thereby prolong their half-lives [1][2][3]. The mechanism is thought to be mediated mainly by endothelial cells that line blood vessels.…”

Section: Introductionmentioning

confidence: 99%

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

2006

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The MHC class I-related neonatal Fc receptor (FcRn) serves in the homeostatic regulation of IgG and albumin by increasing their half-lives. FcRn may bind IgG and albumin simultaneously, and in a pH-dependent manner, with ligand binding at pH 6.0-6.5 and release at pH 7.0-7.4. The FcRn-IgG interaction has been extensively characterized at the amino acid level and shown to depend on conserved histidine residues in the IgG-Fc part that interact with negatively charged residues in the a-2 domain of FcRn. The recently discovered FcRn-albumin interaction remains to be elucidated. Guided by the pH dependence of the FcRn-albumin interaction, we compared the sequence of the FcRn a-2 domain from eleven different species, and identified histidine residues that were conserved in all (H166) or seven (H161) of these. Both residues are located directly opposite to the IgG interaction site in the folded molecule. We did in vitro mutagenesis (H161A or H166A) in combination with interaction studies (ELISA and surface plasmon resonance) with recombinant, soluble, purified receptors and IgG and albumin to investigate the role of the two histidine residues. Our results show clear evidence that the conserved H166 is a key player in the FcRn-albumin interaction.

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Visualizing the Site and Dynamics of IgG Salvage by the MHC Class I-Related Receptor, FcRn

Cited by 271 publications

References 54 publications

Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy

Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

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