A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney.
Clara cell secretory protein (CCSP) is a transport protein for lipophilic substances in bronchio-alveolar fluid, plasma, and uterine secretion. It acts as a carrier for steroid hormones and polychlorinated biphenyl metabolites. Previously, the existence of receptors for uptake of CCSP.ligand complexes into the renal proximal tubules had been suggested. Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells. Binding to cubilin results in uptake and lysosomal degradation of CCSP in cultured cells. Surprisingly, internalization of CCSP is blocked not only by cubilin antagonists but also by antibodies directed against megalin, an endocytic receptor that does not bind CCSP but associates with cubilin. Consistent with a role of both receptors in renal uptake of CCSP in vivo, patients deficient for cubilin or mice lacking megalin exhibit a defect in tubular uptake of the protein and excrete CCSP into the urine. These findings identify a cellular pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and associated ligands.
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
R
R
Burmeister
I M
IM
Boe
A
A
Nykjaer
C
C
Jacobsen
S K
SK
Moestrup
P
P
Verroust
E I
EI
Christensen
J
J
Lund
T E
TE
Willnow
D000818:Animals; D001692:Biological Transport; D015374:Biosensing Techniques; D002462:Cell Membrane / Q000378:metabolism; D004492:Edetic Acid / Q000494:pharmacology; D005198:Fanconi Syndrome / Q000209:etiology / Q000652:urine; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000652:urine; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014598:Uteroglobin / Q000378:metabolism
D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D011506:Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C029486:intrinsic factor-cobalamin receptor; D014598:Uteroglobin; D004492:Edetic Acid