Lysosomal routing of Fc gamma RI from early endosomes requires recruitment of tyrosine kinases.
The high-affinity receptor for immunoglobulin G (Fc gamma RI) plays a central role in the clearance of immune complexes by mediating their internalization and delivery to lysosomes. In monocytic U937 cells, receptor internalization is independent of tyrosine kinase activity. However, the tyrosine kinase inhibitor, genistein, prevents further progress of the receptor to lysosomes and traps it in a sub-plasma membrane early endosome. Similarly, Fc gamma RI expressed in COS cells is able to internalize immune complexes but is unable to translocate to lysosomes. This suggests that Fc gamma RI, whose cytoplasmic tail is devoid of known signalling motifs, must recruit tyrosine kinases via its gamma-chain to achieve lysosomal delivery. We show that a chimera of the extracellular domain of Fc gamma RI and the cytoplasmic tail of the gamma-chain is both internalized and efficiently trafficked to lysosomes. Our study suggests that a key function of the gamma-chain is recruitment of tyrosine kinases to initiate the intracellular signalling pathways required to target Fc gamma RI following immune complex aggregation to lysosomes and not to initiate endocytosis per se.
Department of Medicine & Therapeutics, University of Glasgow, UK.
J C
JC
Norman
P T
PT
Harrison
W
W
Davis
R A
RA
Floto
J M
JM
Allen
D000936:Antigen-Antibody Complex / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000276:immunology*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000276:immunology*; D018613:Microscopy, Confocal; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000936:Antigen-Antibody Complex; D017452:Receptors, IgG; D019833:Genistein; D011505:Protein-Tyrosine Kinases