title: Caveolin interacts with the angiotensin II type 1 receptor during exocytic transport but not at the plasma membrane.
abstract: The mechanisms involved in angiotensin II type 1 receptor (AT1-R) trafficking and membrane localization are largely unknown. In this study, we examined the role of caveolin in these processes. Electron microscopy of plasma membrane sheets shows that the AT1-R is not concentrated in caveolae but is clustered in cholesterol-independent microdomains; upon activation, it partially redistributes to lipid rafts. Despite the lack of AT1-R in caveolae, AT1-R.caveolin complexes are readily detectable in cells co-expressing both proteins. This interaction requires an intact caveolin scaffolding domain because mutant caveolins that lack a functional caveolin scaffolding domain do not interact with AT1-R. Expression of an N-terminally truncated caveolin-3, CavDGV, that localizes to lipid bodies, or a point mutant, Cav3-P104L, that accumulates in the Golgi mislocalizes AT1-R to lipid bodies and Golgi, respectively. Mislocalization results in aberrant maturation and surface expression of AT1-R, effects that are not reversed by supplementing cells with cholesterol. Similarly mutation of aromatic residues in the caveolin-binding site abrogates AT1-R cell surface expression. In cells lacking caveolin-1 or caveolin-3, AT1-R does not traffic to the cell surface unless caveolin is ectopically expressed. This observation is recapitulated in caveolin-1 null mice that have a 55% reduction in renal AT1-R levels compared with controls. Taken together our results indicate that a direct interaction with caveolin is required to traffic the AT1-R through the exocytic pathway, but this does not result in AT1-R sequestration in caveolae. Caveolin therefore acts as a molecular chaperone rather than a plasma membrane scaffold for AT1-R.
authors.affiliation: Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wyse
authors.forename: Ian A
authors.initials: IA
authors.lastname: Prior
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Morrow
authors.forename: Susan
authors.initials: S
authors.lastname: Nixon
authors.forename: Cornelia
authors.initials: C
authors.lastname: Muncke
authors.forename: Teymuras V
authors.initials: TV
authors.lastname: Kurzchalia
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.forename: John F
authors.initials: JF
authors.lastname: Hancock
mesh_terms: D000818:Animals; D051242:Caveolin 1; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane; D002784:Cholesterol / Q000494:pharmacology; D005089:Exocytosis; D006801:Humans; D021962:Membrane Microdomains; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D015388:Organelles / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism*; D014162:Transfection
chemical_list: C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; C495548:Cav3 protein, mouse; D051242:Caveolin 1; D051244:Caveolin 3; D022461:Caveolins; D018832:Molecular Chaperones; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D002784:Cholesterol