title: Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules.
abstract: The neonatal receptor for immunoglobulin G (IgG; FcRn) prevents IgG degradation by efficiently sorting IgG into recycling endosomes and away from lysosomes. When bound to IgG-opsonized antigen complexes, however, FcRn traffics cargo into lysosomes, where antigen processing can occur. Here we address the mechanism of sorting when FcRn is bound to multivalent IgG-opsonized antigens. We find that only the unbound receptor or FcRn bound to monomeric IgG is sorted into recycling tubules emerging from early endosomes. Cross-linked FcRn is never visualized in tubules containing the unbound receptor. Similar results are found for transferrin receptor, suggesting a general mechanism of action. Deletion or replacement of the FcRn cytoplasmic tail does not prevent diversion of trafficking to lysosomes upon cross-linking. Thus physical properties of the lumenal ligand-receptor complex appear to act as key determinants for sorting between the recycling and lysosomal pathways by regulating FcRn entry into recycling tubules.
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Weflen
authors.forename: Nina
authors.initials: N
authors.lastname: Baier
authors.forename: Qing-Juan
authors.initials: QJ
authors.lastname: Tang
authors.forename: Malon
authors.initials: M
authors.lastname: Van den Hof
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
authors.forename: Ramiro H
authors.initials: RH
authors.lastname: Massol
mesh_terms: D000818:Animals; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D011992:Endosomes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006388:Hemagglutinins / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019056:Receptors, Polymeric Immunoglobulin / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D006388:Hemagglutinins; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D019056:Receptors, Polymeric Immunoglobulin; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C100688:Fc receptor, neonatal