A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney

Citation
R. Burmeister et al., A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney, J BIOL CHEM, 276(16), 2001, pp. 13295-13301
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
16
Year of publication
2001
Pages
13295 - 13301
Database
ISI
SICI code
0021-9258(20010420)276:16<13295:ATPFCO>2.0.ZU;2-M
Abstract
Clara cell secretory protein (CCSP) is a transport protein for lipophilic s ubstances in bronchio-alveolar fluid, plasma, and uterine secretion. It act s as a carrier for steroid hormones and polychlorinated biphenyl metabolite s. Previously, the existence of receptors for uptake of CCSP ligand complex es into the renal proximal tubules had been suggested. Using surface plasmo n resonance analysis, we demonstrate that CCSP binds to cubilin, a peripher al membrane protein on the surface of proximal tubular cells. Binding to cu bilin results in uptake and lysosomal degradation of CCSP in cultured cells . Surprisingly, internalization of CCSP is blocked not only by cubilin anta gonists but also by antibodies directed against megalin, an endocytic recep tor 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 t he protein and excrete CCSP into the urine. These findings identify a cellu lar pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and as sociated ligands.