title: Endocytosis-mediated vacuolar accumulation of the human ApoE apolipoprotein-derived ApoEdpL-W antimicrobial peptide contributes to its antifungal activity in Candida albicans.
abstract: The 18-amino-acid cationic, tryptophan-rich ApoEdpL-W peptide derived from human ApoE apolipoprotein was shown to have antifungal activity against pathogenic yeasts of the Candida genus (except C. glabrata). ApoEdpL-W was active against planktonic cells and early-stage biofilms but less active against mature biofilms, possibly because of its affinity for extracellular matrix beta-glucans. Moreover, ApoEdpL-W absorbed to medically relevant materials partially prevented the formation of biofilms on these materials. The exposure of C. albicans cells to sublethal doses of ApoEdpL-W triggered a transcriptional response reminiscent of that associated with the inactivation of the MYO5 gene required for endocytosis as well as the upregulation of amino acid transporter genes. A fluorescent derivative of ApoEdpL-W accumulated at the cytoplasmic membrane and subsequently was translocated to the vacuole. Strikingly, the inactivation of MYO5 or addition of latrunculin, an inhibitor of endocytosis, prevented the vacuolar accumulation of fluorescein-labeled ApoEdpL-W and reduced the antifungal activity of ApoEdpL-W. This, together with the insensitivity of ApoEdpL-W to alterations in membrane fluidity and high salt, suggested that the ApoEdpL-W mode of action was dependent upon vacuolar targeting and differed significantly from that of other antifungal peptides, such as Histatin-5 and Magainin 2.
authors.affiliation: Unite Biologie et Pathogénicité Fongiques-INRA USC 2019, Institut Pasteur, 25-28, rue du Docteur Roux, 75724 Paris Cedex 15, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Rossignol
authors.forename: Bridie
authors.initials: B
authors.lastname: Kelly
authors.forename: Curtis
authors.initials: C
authors.lastname: Dobson
authors.forename: Christophe
authors.initials: C
authors.lastname: d'Enfert
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D024461:Myosin Type I / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010933:Plankton / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D053778:Thiazolidines / Q000494:pharmacology; D014617:Vacuoles / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; C570439:ApoEdpL-W peptide, human; D001057:Apolipoproteins E; D019086:Bridged Bicyclo Compounds, Heterocyclic; C100412:MYO5 protein, S cerevisiae; D010446:Peptide Fragments; D029701:Saccharomyces cerevisiae Proteins; D053778:Thiazolidines; D024461:Myosin Type I; C037067:latrunculin A