Weflen, Andrew W.Baier, NinaTang, Qing-JuanVan den Hof, MalonBlumberg, Richard S.Lencer, Wayne I.Massol, Ramiro H.Gruenberg, Jean E.2019-10-052013Weflen, Andrew W., Nina Baier, Qing-Juan Tang, Malon Van den Hof, Richard S. Blumberg, Wayne I. Lencer, and Ramiro H. Massol. 2013. “Multivalent Immune Complexes Divert FcRn to Lysosomes by Exclusion from Recycling Sorting Tubules.” Edited by Jean E. Gruenberg. Molecular Biology of the Cell 24 (15): 2398–2405. https://doi.org/10.1091/mbc.e13-04-0174.1059-15241939-4586http://nrs.harvard.edu/urn-3:HUL.InstRepos:41483328The 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.en-USJournal Article2019-10-0510.1091/mbc.E13-04-0174