Megalin Acts in Concert with Cubilin to Mediate Endocytosis of High Density Lipoproteins

Cubilin has recently been shown to function as an endocytic receptor for high density lipoproteins (HDL). The lack of apparent transmembrane and cytoplasmic domains in cubilin raises questions as to the means by which it can mediate endocytosis. Since cubilin has been reported to bind the endocytic...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-04, Vol.275 (16), p.12003-12008
Main Authors: Hammad, Samar M., Barth, Jeremy L., Knaak, Christian, Argraves, W.Scott
Format: Article
Language:English
Subjects:
Animals
Cell Line
cubilin
Endocytosis - drug effects
Enzyme-Linked Immunosorbent Assay
Heymann Nephritis Antigenic Complex
Humans
Lipoproteins, HDL - metabolism
megalin
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - pharmacology
Mice
Microscopy, Confocal
oligonucleotides
Oligonucleotides, Antisense - metabolism
Rabbits
Rats
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Swine
Tretinoin - pharmacology
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Summary:Cubilin has recently been shown to function as an endocytic receptor for high density lipoproteins (HDL). The lack of apparent transmembrane and cytoplasmic domains in cubilin raises questions as to the means by which it can mediate endocytosis. Since cubilin has been reported to bind the endocytic receptor megalin, we explored the possibility that megalin acts in conjunction with cubilin to mediate HDL endocytosis. While megalin did not bind to HDL, delipidated HDL, or apoA-I, it was found to copurify with cubilin isolated by HDL-Sepharose affinity chromatography. Cubilin and megalin exhibited coincident patterns of mRNA expression in mouse tissues including the kidney, ileum, thymus, placenta, and yolk sac endoderm. The expression of both receptors in yolk sac endoderm-like cells was inducible by retinoic acid treatment but not by conditions of sterol depletion. Suppression of megalin activity or expression by treatment with either megalin antibodies or megalin antisense oligodeoxynucleotides resulted in inhibition of cubilin-mediated endocytosis of HDL. Furthermore, megalin antisense oligodeoxynucleotide treatment resulted in reduced cell surface expression of cubilin. These data demonstrate that megalin acts together with cubilin to mediate HDL endocytosis and further suggest that megalin may play a role in the intracellular trafficking of cubilin.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.16.12003