The neonatal fragment crystallizable (Fc) receptor (also FcRn, IgG receptor FcRn large subunit p51, or Brambell receptor) is a protein that in humans is encoded by the FCGRT gene

January 30, 2024
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It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin. In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother’s milk, leading to its name as the neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother’s IgG to the growing fetus. FcRn has also been shown to play a role in regulating IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF, and down-regulated by IFN-γ.

Interactions of FcRn with IgG and serum albumin

In addition to binding to IgG, FCGRT has been shown to interact with human serum albumin. FcRn-mediated transcytosis of IgG across epithelial cells is possible because FcRn binds IgG at acidic pH (<6.5) but not at neutral or higher pH. The binding site for FcRn on IgG has been mapped using functional and structural studies, and involves in the interaction of relatively well conserved histidine residues on IgG with acidic residues on FcRn.

FcRn-mediated recycling and transcytosis of IgG and serum albumin

FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation of these proteins in endothelial cells and bone-marrow derived cells. The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn. IgG, serum albumin and other serum proteins are continuously internalized into cells through pinocytosis.

In cellular biology, pinocytosis, otherwise known as fluid endocytosis and bulk-phase pinocytosis, is a mode of endocytosis in which small molecules dissolved in extracellular fluid are brought into the cell through an invagination of the cell membrane, resulting in their containment within a small vesicle inside the cell. These pinocytotic vesicles then typically fuse with early endosomes to hydrolyze (break down) the particles.[citation needed] Pinocytosis is variably subdivided into categories depending on the molecular mechanism and the fate of the internalized molecules.

Function

In humans, this process occurs primarily for absorption of fat droplets. In endocytosis the cell plasma membrane extends and folds around desired extracellular material, forming a pouch that pinches off creating an internalized vesicle. The invaginated pinocytosis vesicles are much smaller than those generated by phagocytosis. The vesicles eventually fuse with the lysosome, whereupon the vesicle contents are digested. Pinocytosis involves a considerable investment of cellular energy in the form of ATP.

Pinocytosis and ATP

Pinocytosis is used primarily for clearing extracellular fluids (ECF) and as part of immune surveillance. In contrast to phagocytosis, it generates very small amounts of ATP from the wastes of alternative substances such as lipids (fat).[citation needed] Unlike receptor-mediated endocytosis, pinocytosis is nonspecific in the substances that it transport: the cell takes in surrounding fluids, including all solutes present.

Etymology and pronunciation

The word pinocytosis uses combining forms of pino- + cyto- + -osis, all Neo-Latin from Greek, reflecting píno, to drink, and cytosis. The term was proposed by W. H. Lewis in 1931.

Non-specific, adsorptive pinocytosis

Non-specific, adsorptive pinocytosis is a form of endocytosis, a process in which small particles are taken in by a cell by splitting off small vesicles from the cell membrane. Cationic proteins bind to the negative cell surface and are taken up via the clathrin-mediated system, thus the uptake is intermediate between receptor-mediated endocytosis and non-specific, non-adsorptive pinocytosis. The clathrin-coated pits occupy about 2% of the surface area of the cell and only last about a minute, with an estimated 2500 leaving the average cell surface each minute. The clathrin coats are lost almost immediately, and the membrane is subsequently recycled to the cell surface.

  • Alberts, Johnson, Lewis, Raff, Roberts, Walter: “Molecular Biology of the Cell”, Fourth Edition, Copyright 2002 P.748

Macropinocytosis

Macropinocytosis is a clathrin-independent endocytic mechanism that can be activated in practically all animal cells, resulting in uptake. In most cell types, it does not occur continuously but rather is induced for a limited time in response to cell-surface receptor activation by specific cargoes, including growth factors, ligands of integrins, and apoptotic cell remnants. These ligands activate a complex signaling pathway, resulting in a change in actin dynamics and the formation of cell-surface protrusions of filopodia and lamellopodia, commonly called ruffles. When ruffles collapse back onto the membrane, large fluid-filled endocytic vesicles form called macropinosomes, which can transiently increase the bulk fluid uptake of a cell by up to tenfold. Macropinocytosis is a solely degradative pathway: macropinosomes acidify and then fuse with late endosomes or endolysosomes, without recycling their cargo back to the plasma membrane.

Some bacteria and viruses have evolved to induce macropinocytosis as a mechanism for entering host cells. Some of these can stop the degradation processes in order to survive inside the macropinosome, which may transform into smaller and long-lasting vacuoles containing the viruses or bacteria (some of which may replicate inside), or simply escape through the wall of the macropinosome when inside. For example, the gut pathogen Salmonella typhimurium injects toxins into the host cell in order to induce macropinocytosis as a form of uptake, inhibits the degradation of the macropinosome, and forms a salmonella-containing vacuole, or SCV, wherein it can replicate.

See also

  • Campbell, Reece, Mitchell: “Biology”, Sixth Edition, Copyright 2002 P. 151
  • Marshall, Ben, Incredible Biological Advancements of the 20th Century, Copyright 2001 p. 899
  • Alrt, Pablo, Global Society Harvard study, copyright 2003 p. 189
  • Brooker, Robert: “Biology”, Second Edition, Copyright 2011 p. 116
  • Cherrr, Malik, The Only Edition, Copyright 2012, p. 256
  • Abbas, Abul, et al. “Basic Immunology: Functions and Disorders of the Immune System.” 5th ed. Elsevier, 2016. p. 69

Generally, internalized serum proteins are transported from early endosomes to lysosomes, where they are degraded. Following entry into cells, the two most abundant serum proteins, IgG and serum albumin, are bound by FcRn at the slightly acidic pH (<6.5) within early (sorting) endosomes, sorted and recycled to the cell surface where they are released at the neutral pH (>7.0) of the extracellular environment. In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation. This cellular mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin and transport of these ligands across cellular barriers. In addition, for cell types bathed in an acidic environment such as the slightly acidic intestinal lumen, cell surface FcRn can bind to IgG, transport bound ligand across intestinal epithelial cells followed by release at the near neutral pH at the basolateral surface.

Diverse roles for FcRn in various organs

FcRn is expressed on antigen-presenting leukocytes such as dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria. In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier. Current studies are investigating FcRn in the liver because there are relatively low concentrations of both IgG and albumin in liver bile despite high concentrations in the blood. Studies have also shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.

Diagram showing the basic physiologic mechanisms of the kidney

Podocytes are cells in Bowman’s capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman’s capsule, the third layer through which filtration of blood takes place. Bowman’s capsule filters the blood, retaining large molecules such as proteins while smaller molecules such as water, salts, and sugars are filtered as the first step in the formation of urine. Although various viscera have epithelial layers, the name visceral epithelial cells usually refers specifically to podocytes, which are specialized epithelial cells that reside in the visceral layer of the capsule. The podocytes have long foot processes called pedicels, for which the cells are named (podo- + -cyte). The pedicels wrap around the capillaries and leave slits between them. Blood is filtered through these slits, each known as a filtration slit, slit diaphragm, or slit pore. Several proteins are required for the pedicels to wrap around the capillaries and function. When infants are born with certain defects in these proteins, such as nephrin and CD2AP, their kidneys cannot function. People have variations in these proteins, and some variations may predispose them to kidney failure later in life. Nephrin is a zipper-like protein that forms the slit diaphragm, with spaces between the teeth of the zipper big enough to allow sugar and water through but too small to allow proteins through. Nephrin defects are responsible for congenital kidney failure. CD2AP regulates the podocyte cytoskeleton and stabilizes the slit diaphragm.

Structure

Podocytes are found lining the Bowman’s capsules in the nephrons of the kidney. The foot processes known as pedicels that extend from the podocytes wrap themselves around the capillaries of the glomerulus to form the filtration slits. The pedicels increase the surface area of the cells enabling efficient ultrafiltration. Podocytes secrete and maintain the basement membrane.

Scheme of filtration barrier (blood-urine) in the kidney.
A. The endothelial cells of the glomerulus; 1. pore (fenestra).
B. Glomerular basement membrane: 1. lamina rara interna 2. lamina densa 3. lamina rara externa
C. Podocytes: 1. enzymatic and structural protein 2. filtration slit 3. diaphragma

There are numerous coated vesicles and coated pits along the basolateral domain of the podocytes which indicate a high rate of vesicular traffic. Podocytes possess a well-developed endoplasmic reticulum and a large Golgi apparatus, indicative of a high capacity for protein synthesis and post-translational modifications. There is also growing evidence of a large number of multivesicular bodies and other lysosomal components seen in these cells, indicating a high endocytic activity.

Function

Pedicels of podocytes interdigitating to create numerous filtration slits around glomerular capillaries in 5000x electron micrograph

Podocytes have primary processes called trabeculae, which wrap around the glomerular capillaries. The trabeculae in turn have secondary processes called pedicels. Pedicels interdigitate, thereby giving rise to thin gaps called filtration slits. The slits are covered by slit diaphragms which are composed of a number of cell-surface proteins including nephrin, podocalyxin, and P-cadherin, which restrict the passage of large macromolecules such as serum albumin and gamma globulin and ensure that they remain in the bloodstream. Proteins that are required for the correct function of the slit diaphragm include nephrin, NEPH1, NEPH2, podocin, CD2AP. and FAT1.

Small molecules such as water, glucose, and ionic salts are able to pass through the filtration slits and form an ultrafiltrate in the tubular fluid, which is further processed by the nephron to produce urine. Podocytes are also involved in regulation of glomerular filtration rate (GFR). When podocytes contract, they cause closure of filtration slits. This decreases the GFR by reducing the surface area available for filtration.

Clinical significance

Morphologic patterns of podocyte injury. Cutrim ÉMM, Neves PDMM, Campos MAG, Wanderley DC, Teixeira-Júnior AAL, Muniz MPR; et al. (2022). “Collapsing Glomerulopathy: A Review by the Collapsing Brazilian Consortium”. Front Med (Lausanne). 9: 846173. doi:10.3389/fmed.2022.846173. PMC 8927620. PMID 35308512.
– CC-BY 4.0 license

A loss of the foot processes of the podocytes (i.e., podocyte effacement) is a hallmark of minimal change disease, which has therefore sometimes been called foot process disease.

Disruption of the filtration slits or destruction of the podocytes can lead to massive proteinuria, where large amounts of protein are lost from the blood. An example of this occurs in the congenital disorder Finnish-type nephrosis, which is characterised by neonatal proteinuria leading to end-stage kidney failure. This disease has been found to be caused by a mutation in the nephrin gene.

In 2002 Professor Moin Saleem at the University of Bristol made the first conditionally immortalised human podocyte cell line.[further explanation needed] This meant that podocytes could be grown and studied in the lab. Since then many discoveries have been made. Nephrotic syndrome occurs when there is a breakdown of the glomerular filtration barrier. The podocytes form one layer of the filtration barrier. Genetic mutations can cause podocyte dysfunction leading to an inability of the filtration barrier to restrict urinary protein loss. There are currently 53 genes known to play a role in genetic nephrotic syndrome. In idiopathic nephrotic syndrome, there is no known genetic mutation. It is thought to be caused by a hitherto unknown circulating permeability factor. Recent evidence suggests that the factor could be released by T-cells or B-cells, podocyte cell lines can be treated with plasma from patients with nephrotic syndrome to understand the specific responses of the podocyte to the circulating factor. There is growing evidence that the circulating factor could be signalling to the podocyte via the PAR-1 receptor.[further explanation needed]

Presence of podocytes in urine has been proposed as an early diagnostic marker for preeclampsia.

See also

Half-life extension of therapeutic proteins

The identification of FcRn as a central regulator of IgG levels led to the engineering of IgG-FcRn interactions to increase in vivo persistence of IgG. For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has been approved for the treatment of autoimmunity and a half-life extended antibody cocktail (Evusheld) with ‘YTE’ mutations is used for the prophylaxis of SARS-CoV2. Engineering of albumin-FcRn interactions has also generated albumin variants with increased in vivo half-lives. It has also been shown that conjugation of some drugs to the Fc region of IgG or serum albumin to generate fusion proteins significantly increases their half-life.

There are several drugs on the market that have Fc portions fused to the effector proteins in order to increase their half-lives through FcRn-mediated recycling. They include: Amevive (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept). Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.

Targeting FcRn to treat autoimmune disease

Multiple autoimmune disorders are caused by the binding of IgG to self antigens. Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on these pathogenic antibodies and promote autoimmune disease. Therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of disease-causing IgG autoantibodies from the body. One such therapy is the infusion of intravenous immunoglobulin (IVIg) to saturate FcRn’s IgG recycling capacity and proportionately reduce the levels of disease-causing IgG autoantibody binding to FcRn, thereby increasing disease-causing IgG autoantibody removal. More recent approaches involve the strategy of blocking the binding of IgG to FcRn by delivering antibodies that bind with high affinity to this receptor through their Fc region or variable regions. These engineered Fc fragments or antibodies are being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and skin blistering diseases (pemphigus), and the Fc-based inhibitor, efgartigimod, based on the ‘Abdeg’ technology was recently approved (as ‘Vyvgart’) for the treatment of generalized MYASTHENIA GRAVIS in December 2021.

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Further reading

External links

Transmembrane receptors: immunoglobulin superfamily immune receptors

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