Binding of monomeric immunoglobulin G triggers Fc gamma RI-mediated endocytosis.
Cross-linking of leukocyte Fc receptors specific for IgG (Fc gamma Rs) by multivalent IgG complexes triggers a wide range of immune functions. Many of these responses can also be stimulated in vitro using anti-Fc gamma R monoclonal antibody-containing complexes. This observation has suggested that cross-linking is the key event and that binding of IgG, which in itself does not elicit a response, is functionally passive. However, in this study we show that binding of monomeric IgG to the human high affinity receptor, Fc gamma RI, is itself sufficient to permit the receptor to enter an internalization-recycling pathway, which has a small intracellular pool. Unoccupied Fc gamma RI is not internalized and recycled in this manner. This finding may be explained by the previous observation that there is a physical association between Fc gamma RI and the cytoskeletal component, actin-binding protein (non-muscle filamin; ABP-280), which is disrupted upon IgG binding. Thus, in the absence of IgG, Fc gamma RI may be physically excluded from the endocytic pathway by tethering to the cytoskeleton. The role of cross-linking is to divert Fc gamma RI-IgG complexes from the recycling pathway, causing their retention and subsequent degradation within the cell. In contrast to Fc gamma RII-mediated endocytosis, intracellular accumulation of cross-linked Fc gamma RI-IgG complexes is not sensitive to inhibition by genistein, suggesting that the process is independent of tyrosine kinase activity.
Harrison
P T
PT
Physiological Laboratory, University of Cambridge, United Kingdom.
Davis
W
W
Norman
J C
JC
Hockaday
A R
AR
Allen
J M
JM
D000936:Antigen-Antibody Complex; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008854:Microscopy, Electron; D011319:Primaquine / Q000494:pharmacology; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; D011319:Primaquine