Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Apr 1;163(4):952–971. doi: 10.1084/jem.163.4.952

Transport of macrophage Fc receptors and Fc receptor-bound ligands to lysosomes

PMCID: PMC2188083  PMID: 3950548

Abstract

Mouse macrophage Fc receptors specific for IgG1/IgG2b mediate the binding and pinocytic uptake of soluble IgG-containing antibody-antigen complexes. Internalization of these multivalent IgG complexes is accompanied not only by the intracellular degradation of the ligand, but also by a net decrease in the number of plasma membrane Fc receptors and an accelerated rate of receptor turnover. In contrast, internalized receptors bound to a monovalent ligand, the high affinity Fab fragment of the antireceptor mAb 2.4G2, escape degradation by rapidly recycling to the cell surface. In this paper, we have characterized the intracellular pathway involved in the endocytosis and transport of Fc receptors in the J774 macrophage cell line. The results show that the uptake of multivalent ligands follows the normal pathway of receptor-mediated endocytosis: internalization in clathrin-coated pits and coated vesicles, delivery to endosomes, and finally to acid hydrolase-rich lysosomes. Immunoprecipitation of radiolabeled receptor from Percoll density gradients showed that endocytosis of the IgG complexes also results in the concomitant transport of the receptor to lysosomes. Although uptake of the monovalent Fab fragment had no detectable effect on intracellular receptor distribution, preparations of 2.4G2 Fab rendered multivalent by adsorption to colloidal gold were as effective as the IgG complexes at causing lysosomal accumulation of internalized receptors. Thus, it is likely that the down-regulation and degradation of Fc receptors which occurs during the endocytosis of antibody-antigen complexes is due to the transport of internalized receptors to lysosomes. Moreover, the ability of certain Fc receptor- bound ligands to interfere with receptor recycling and trigger lysosomal transport seems to depend on ligand valency rather than on the presence or absence of Fc domains on intact IgG molecules.

Full Text

The Full Text of this article is available as a PDF (2.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson R. G., Brown M. S., Beisiegel U., Goldstein J. L. Surface distribution and recycling of the low density lipoprotein receptor as visualized with antireceptor antibodies. J Cell Biol. 1982 Jun;93(3):523–531. doi: 10.1083/jcb.93.3.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ascoli M. Lysosomal accumulation of the hormone-receptor complex during receptor-mediated endocytosis of human choriogonadotropin. J Cell Biol. 1984 Oct;99(4 Pt 1):1242–1250. doi: 10.1083/jcb.99.4.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Björk I., Petersson B. A., Sjöquist J. Some physiochemical properties of protein A from Staphylococcus aureus. Eur J Biochem. 1972 Sep 25;29(3):579–584. doi: 10.1111/j.1432-1033.1972.tb02024.x. [DOI] [PubMed] [Google Scholar]
  4. Brown M. S., Anderson R. G., Goldstein J. L. Recycling receptors: the round-trip itinerary of migrant membrane proteins. Cell. 1983 Mar;32(3):663–667. doi: 10.1016/0092-8674(83)90052-1. [DOI] [PubMed] [Google Scholar]
  5. Galloway C. J., Dean G. E., Marsh M., Rudnick G., Mellman I. Acidification of macrophage and fibroblast endocytic vesicles in vitro. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3334–3338. doi: 10.1073/pnas.80.11.3334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Green S. A., Plutner H., Mellman I. Biosynthesis and intracellular transport of the mouse macrophage Fc receptor. J Biol Chem. 1985 Aug 15;260(17):9867–9874. [PubMed] [Google Scholar]
  7. Harford J., Bridges K., Ashwell G., Klausner R. D. Intracellular dissociation of receptor-bound asialoglycoproteins in cultured hepatocytes. A pH-mediated nonlysosomal event. J Biol Chem. 1983 Mar 10;258(5):3191–3197. [PubMed] [Google Scholar]
  8. Hopkins C. R., Trowbridge I. S. Internalization and processing of transferrin and the transferrin receptor in human carcinoma A431 cells. J Cell Biol. 1983 Aug;97(2):508–521. doi: 10.1083/jcb.97.2.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hubbard A. L., Cohn Z. A. Externally disposed plasma membrane proteins. I. Enzymatic iodination of mouse L cells. J Cell Biol. 1975 Feb;64(2):438–460. doi: 10.1083/jcb.64.2.438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kielian M. C., Cohn Z. A. Intralysosomal accumulation of polyanions. II. Polyanion internalization and its influence on lysosomal pH and membrane fluidity. J Cell Biol. 1982 Jun;93(3):875–882. doi: 10.1083/jcb.93.3.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Leslie R. G. Macrophage handling of soluble immune complexes. Ingestion and digestion of surface-bound complexes at 4, 20 and 37 degrees C. Eur J Immunol. 1980 May;10(5):323–333. doi: 10.1002/eji.1830100503. [DOI] [PubMed] [Google Scholar]
  12. McKanna J. A., Haigler H. T., Cohen S. Hormone receptor topology and dynamics: morphological analysis using ferritin-labeled epidermal growth factor. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5689–5693. doi: 10.1073/pnas.76.11.5689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mellman I. S., Plutner H., Steinman R. M., Unkeless J. C., Cohn Z. A. Internalization and degradation of macrophage Fc receptors during receptor-mediated phagocytosis. J Cell Biol. 1983 Mar;96(3):887–895. doi: 10.1083/jcb.96.3.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mellman I. S., Steinman R. M., Unkeless J. C., Cohn Z. A. Selective iodination and polypeptide composition of pinocytic vesicles. J Cell Biol. 1980 Sep;86(3):712–722. doi: 10.1083/jcb.86.3.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mellman I. S., Unkeless J. C. Purificaton of a functional mouse Fc receptor through the use of a monoclonal antibody. J Exp Med. 1980 Oct 1;152(4):1048–1069. doi: 10.1084/jem.152.4.1048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mellman I., Plutner H. Internalization and degradation of macrophage Fc receptors bound to polyvalent immune complexes. J Cell Biol. 1984 Apr;98(4):1170–1177. doi: 10.1083/jcb.98.4.1170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mellman I., Plutner H., Ukkonen P. Internalization and rapid recycling of macrophage Fc receptors tagged with monovalent antireceptor antibody: possible role of a prelysosomal compartment. J Cell Biol. 1984 Apr;98(4):1163–1169. doi: 10.1083/jcb.98.4.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Merion M., Sly W. S. The role of intermediate vesicles in the adsorptive endocytosis and transport of ligand to lysosomes by human fibroblasts. J Cell Biol. 1983 Mar;96(3):644–650. doi: 10.1083/jcb.96.3.644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ohkuma S., Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3327–3331. doi: 10.1073/pnas.75.7.3327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schreiber A. B., Libermann T. A., Lax I., Yarden Y., Schlessinger J. Biological role of epidermal growth factor-receptor clustering. Investigation with monoclonal anti-receptor antibodies. J Biol Chem. 1983 Jan 25;258(2):846–853. [PubMed] [Google Scholar]
  21. Schwartz A. L., Fridovich S. E., Lodish H. F. Kinetics of internalization and recycling of the asialoglycoprotein receptor in a hepatoma cell line. J Biol Chem. 1982 Apr 25;257(8):4230–4237. [PubMed] [Google Scholar]
  22. Steinman R. M., Mellman I. S., Muller W. A., Cohn Z. A. Endocytosis and the recycling of plasma membrane. J Cell Biol. 1983 Jan;96(1):1–27. doi: 10.1083/jcb.96.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Unkeless J. C. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 1979 Sep 19;150(3):580–596. doi: 10.1084/jem.150.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Unkeless J. C., Eisen H. N. Binding of monomeric immunoglobulins to Fc receptors of mouse macrophages. J Exp Med. 1975 Dec 1;142(6):1520–1533. doi: 10.1084/jem.142.6.1520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Unkeless J. C., Fleit H., Mellman I. S. Structural Aspects and Heterogeneity of Immunoglobulin Fc Receptors. Adv Immunol. 1981;31:247–270. doi: 10.1016/s0065-2776(08)60922-0. [DOI] [PubMed] [Google Scholar]
  26. Unkeless J. C. The presence of two Fc receptors on mouse macrophages: evidence from a variant cell line and differential trypsin sensitivity. J Exp Med. 1977 Apr 1;145(4):931–945. doi: 10.1084/jem.145.4.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Willingham M. C., Hanover J. A., Dickson R. B., Pastan I. Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells. Proc Natl Acad Sci U S A. 1984 Jan;81(1):175–179. doi: 10.1073/pnas.81.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. van Renswoude J., Bridges K. R., Harford J. B., Klausner R. D. Receptor-mediated endocytosis of transferrin and the uptake of fe in K562 cells: identification of a nonlysosomal acidic compartment. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6186–6190. doi: 10.1073/pnas.79.20.6186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. von Figura K., Gieselmann V., Hasilik A. Antibody to mannose 6-phosphate specific receptor induces receptor deficiency in human fibroblasts. EMBO J. 1984 Jun;3(6):1281–1286. doi: 10.1002/j.1460-2075.1984.tb01963.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES