MYELOMA LIGHT-CHAINS ARE LIGANDS FOR CUBILIN (GP280)

Although myeloma light chains are known to undergo receptor-mediated e ndocytosis in the kidney, the molecular identity of the receptor has n ot been characterized. We examined the interaction between cubilin (gp 280) and four species of light chains isolated from the urine of patie nts with multiple myeloma. Four lines of evidence identify cubilin, a giant glycoprotein receptor, which is restricted in distribution to en docytic scavenger pathways and which has potent effects on endosomal t rafficking, as a potentially physiologically relevant binding site for light chains: I) light chains coeluted during immunoaffinity purifica tion of cubilin; 2) polyclonal antisera to cubilin but not control ser a, displaced human light chain binding from rat renal brush-border mem branes; 3) cubilin bound to multiple species of light chains during su rface plasmon resonance; 4) anti-cubilin antiserum interfered with lig ht chain endocytosis by visceral yolk sac epithelial cells. However, b oth binding of light chains to brush-border membranes and endocytosis of light chains by yolk sac epithelial cells were only partially inhib ited by anticubilin antibodies, suggesting presence of additional or a lternate binding sites for light chains. Excess light chain had a pote nt inhibitory effect on endosomal fusion in vitro. Binding showed dose and time-dependent saturability with low-affinity, high-capacity equi librium binding parameters. These data demonstrate that cubilin plays a role in the endocytosis and trafficking of light chains in renal pro ximal tubule cells.