title: Annexin A6-induced alterations in cholesterol transport and caveolin export from the Golgi complex.
abstract: Annexin A6 (AnxA6) belongs to a family of Ca(2+)-dependent membrane-binding proteins and is involved in the regulation of endocytic and exocytic pathways. We previously demonstrated that AnxA6 regulates receptor-mediated endocytosis and lysosomal targeting of low-density lipoproteins and translocates to cholesterol-enriched late endosomes (LE). As cholesterol modulates the membrane binding and the cellular location of AnxA6, but also affects the intracellular distribution of caveolin, we investigated the localization and trafficking of caveolin in AnxA6-expressing cells. Here, we show that cells expressing high levels of AnxA6 are characterized by an accumulation of caveolin-1 (cav-1) in the Golgi complex. This is associated with a sequestration of cholesterol in the LE and lower levels of cholesterol in the Golgi and the plasma membrane, both likely contributing to retention of caveolin in the Golgi apparatus and a reduced number of caveolae at the cell surface. Further strengthening these findings, knock down of AnxA6 and the ectopic expression of the Niemann-Pick C1 protein in AnxA6-overexpressing cells restore the cellular distribution of cav-1 and cholesterol, respectively. In summary, this study demonstrates that elevated expression levels of AnxA6 perturb the intracellular distribution of cholesterol, which indirectly inhibits the exit of caveolin from the Golgi complex.
authors.affiliation: Departament de Biologia Cellular, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036-Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Cubells
authors.forename: Sandra
authors.initials: S
authors.lastname: Vilà de Muga
authors.forename: Francesc
authors.initials: F
authors.lastname: Tebar
authors.forename: Peta
authors.initials: P
authors.lastname: Wood
authors.forename: Rachael
authors.initials: R
authors.lastname: Evans
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ingelmo-Torres
authors.forename: Maria
authors.initials: M
authors.lastname: Calvo
authors.forename: Katharina
authors.initials: K
authors.lastname: Gaus
authors.forename: Albert
authors.initials: A
authors.lastname: Pol
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
mesh_terms: D000818:Animals; D017317:Annexin A6 / Q000378:metabolism*; D001692:Biological Transport; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D022461:Caveolins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism