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Flotillin-dependent membrane microdomains are required for functional phagolysosomes against fungal infections

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dc.contributor.authorSchmidt, Franziska
dc.contributor.authorThywißen, Andreas
dc.contributor.authorGoldmann, Marie
dc.contributor.authorCunha, Cristina
dc.contributor.authorCseresnyés, Zoltán
dc.contributor.authorSchmidt, Hella
dc.contributor.authorRafiq, Muhammad
dc.contributor.authorGaliani, Silvia
dc.contributor.authorGräler, Markus H.
dc.contributor.authorChamilos, Georgios
dc.contributor.authorLacerda, João
dc.contributor.authorCampos, António
dc.contributor.authorEggeling, Christian
dc.contributor.authorFigge, Marc Thilo
dc.contributor.authorHeinekamp, Thorsten
dc.contributor.authorFiller, Scott G.
dc.contributor.authorCarvalho, Agostinho
dc.contributor.authorBrakhage, Axel A.
dc.date.accessioned2021-04-28T14:40:19Z
dc.date.available2021-04-28T14:40:19Z
dc.date.issued2020
dc.description© 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)pt_PT
dc.description.abstractLipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid-raft microdomains are essential components of phagolysosomal membranes of macrophages and depend on flotillins. Genetic deletion of flotillins demonstrates that the assembly of both major defense complexes vATPase and NADPH oxidase requires membrane microdomains. Furthermore, we describe a virulence mechanism leading to dysregulation of membrane microdomains by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus resulting in reduced phagolysosomal acidification. We show that phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ ions and that inhibition of Ca2+-dependent calmodulin activity led to reduced lipid-raft formation. We identify a single-nucleotide polymorphism in the human FLOT1 gene resulting in heightened susceptibility for invasive aspergillosis in hematopoietic stem cell transplant recipients. Collectively, flotillin-dependent microdomains on the phagolysosomal membrane play an essential role in protective antifungal immunity.pt_PT
dc.description.sponsorshipThis work was supported by the International Leibniz Research School ( ILRS ) as part of the excellence graduate school Jena School for Microbial Communication (JSMC) funded by the Deutsche Forschungsgemeinschaft ( DFG ), the Leibniz Science Campus “InfectoOptics,” and the DFG -funded CRC 127 8 “PolyTarget” (project B02 to A.A.B. and Z01 to M.T.F.). C.C. and A.C were supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund ( FEDER ) ( NORTE-01-0145-FEDER-000013 ), and by the Fundação para a Ciência e Tecnologia ( FCT ) ( SFRH/BPD/96176/2013 to C.C. and IF/00735/2014 to A.C.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Rep. 2020 Aug 18;32(7):108017pt_PT
dc.identifier.doi10.1016/j.celrep.2020.108017pt_PT
dc.identifier.issn2211-1247
dc.identifier.urihttp://hdl.handle.net/10451/47593
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationNORTE-01-0145-FEDER-000013pt_PT
dc.relationTHE ROLE OF INFLAMMASOME ACTIVATION IN HOST IMMUNITY TO FUNGAL INFECTION - The inflammasome-microbiota interplay in antifungal immunity
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/cell-reports - https://www.cell.com/cell-reports/homept_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectAspergillus fumigatuspt_PT
dc.subjectNADPH oxidasept_PT
dc.subjectCalcium signalingpt_PT
dc.subjectConidial melaninpt_PT
dc.subjectFlotillinpt_PT
dc.subjectFungal pathogenesispt_PT
dc.subjectMacrophagept_PT
dc.subjectMembrane microdomainspt_PT
dc.subjectPhagolysosomept_PT
dc.subjectvATPasept_PT
dc.titleFlotillin-dependent membrane microdomains are required for functional phagolysosomes against fungal infectionspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BPD/96176/2013
oaire.awardTitleTHE ROLE OF INFLAMMASOME ACTIVATION IN HOST IMMUNITY TO FUNGAL INFECTION - The inflammasome-microbiota interplay in antifungal immunity
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F96176%2F2013/PT
oaire.citation.issue7pt_PT
oaire.citation.titleCell Reportspt_PT
oaire.citation.volume32pt_PT
person.familyNameLacerda
person.givenNameJoão
person.identifier559297
person.identifier.ciencia-id6412-2B63-2364
person.identifier.orcid0000-0003-1351-2809
person.identifier.scopus-author-id6603819609
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationafb302b1-8272-48de-b347-cb5b54a0a3da
relation.isAuthorOfPublication.latestForDiscoveryafb302b1-8272-48de-b347-cb5b54a0a3da
relation.isProjectOfPublicationf53289b8-69d0-42bb-b3a1-e7533a1d0951
relation.isProjectOfPublication.latestForDiscoveryf53289b8-69d0-42bb-b3a1-e7533a1d0951

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