title: Human IgA as a heterovalent ligand: switching from the asialoglycoprotein receptor to secretory component during transport across the rat hepatocyte.
abstract: Asialoglycoproteins are taken up by the rat liver for degradation; rat polymeric IgA is taken up via a separate receptor, secretory component (SC), for quantitative delivery to bile. There is negligible uptake of these ligands by the converse receptor, and only a low level of missorting of ligands to opposite destinations. The two pathways are not cross-inhibitable and operate independently (Schiff, J.M., M. M. Fisher, and B. J. Underdown, 1984, J. Cell Biol., 98:79-89). We report here that when human IgA is presented as a ligand in the rat, it is processed using elements of both pathways. To study this in detail, different IgA fractions were prepared using two radiolabeling methods that provide separate probes for degradation or re-secretion. Behavior of intravenously injected human polymeric IgA in the rat depended on its binding properties. If deprived of SC binding activity by affinity adsorption or by reduction and alkylation, greater than 80% of human IgA was degraded in hepatic lysosomes; radioactive catabolites were released into bile by a leupeptin-inhibitable process. If prevented from binding to the asialoglycoprotein receptor by competition or by treatment with galactose oxidase, human IgA was cleared and transported to bile directly via SC, but its uptake was about fivefold slower than rat IgA. Untreated human IgA was taken up rapidly by the asialoglycoprotein receptor, but depended on SC binding to get to bile: the proportion secreted correlated 1:1 with SC binding activity determined in vitro, and the IgA was released into bile with SC still attached. These results demonstrate that human IgA is normally heterovalent: it is first captured from blood by the asialoglycoprotein receptor, but escapes the usual fate of asialoglycoproteins by switching to SC during transport. Since the biliary transit times of native human and rat IgA are the same, it is probable that the receptor switching event occurs en route. This implies that the two receptors briefly share a common intracellular compartment.
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor; D001646:Bile / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002451:Cell Compartmentation; D005692:Galactose Oxidase / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011961:Receptors, Fc; D011971:Receptors, Immunologic / Q000378:metabolism*; D012635:Secretory Component / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D037263:Asialoglycoprotein Receptor; C045281:IgA receptor; D007070:Immunoglobulin A; D007128:Immunoglobulin Fragments; D007976:Leupeptins; D008024:Ligands; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D012635:Secretory Component; C034639:polymeric IgA; D005692:Galactose Oxidase; C032854:leupeptin