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Calcium sequestration by fungal melanin inhibits calcium–calmodulin signalling to prevent LC3-associated phagocytosis

2018Journal article Restricted access
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dc.contributor.authorKyrmizi, Irene
dc.contributor.authorFerreira, Helena
dc.contributor.authorCarvalho, Agostinho
dc.contributor.authorFigueroa, Julio Alberto Landero
dc.contributor.authorZarmpas, Pavlos
dc.contributor.authorCunha, Cristina
dc.contributor.authorAkoumianaki, Tonia
dc.contributor.authorStylianou, Kostas
dc.contributor.authorDeepe, George S.
dc.contributor.authorSamonis, George
dc.contributor.authorLacerda, João
dc.contributor.authorCampos, António
dc.contributor.authorKontoyiannis, Dimitrios P.
dc.contributor.authorMihalopoulos, Nikolaos
dc.contributor.authorKwon-Chung, Kyung J.
dc.contributor.authorEl-Benna, Jamel
dc.contributor.authorValsecchi, Isabel
dc.contributor.authorBeauvais, Anne
dc.contributor.authorBrakhage, Axel A.
dc.contributor.authorNeves, Nuno M.
dc.contributor.authorLatge, Jean-Paul
dc.contributor.authorChamilos, Georgios
dc.date.accessioned2022-11-25T15:13:52Z
dc.date.available2022-11-25T15:13:52Z
dc.date.issued2018
dc.description© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reservedpt_PT
dc.description.abstractLC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway regulated by Rubicon, with an emerging role in immune homeostasis and antifungal host defence. Aspergillus cell wall melanin protects conidia (spores) from killing by phagocytes and promotes pathogenicity through blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of LAP. However, the signalling regulating LAP upstream of Rubicon and the mechanism of melanin-induced inhibition of this pathway remain incompletely understood. Herein, we identify a Ca2+ signalling pathway that depends on intracellular Ca2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca2+ release from phagosome lumen and calmodulin (CaM) recruitment, as a master regulator of Rubicon, the phagocyte NADPH oxidase NOX2 and other molecular components of LAP. Furthermore, we provide genetic evidence for the physiological importance of Ca2+-CaM signalling in aspergillosis. Finally, we demonstrate that Ca2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca2+-CaM signalling to inhibit LAP. These findings reveal the important role of Ca2+-CaM signalling in antifungal immunity and identify an immunological function of Ca2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.pt_PT
dc.description.sponsorshipI.K.’s work is supported by the Onassis Foundation under the ‘Special Grant and Support Program for Scholars’ Association Members’ (Grant no. R ZM 003-1/2016-2017); G.C. was supported by grants from the Greek State Scholarship Foundation (I.K.Y.), the Hellenic General Secretariat for Research and Technology-Excellence program (ARISTEIA) and a Research Grant from Institut Mérieux; J.P.L. was supported by European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 260338 ALLFUN and ANR-10-BLAN-1309 HYDROPHOBIN, and the Association Vaincre La Mucoviscidose (RF20140501052/1/1/141); H.F. and N.M.N. were supported by the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e Tecnologia (FCT) project SPARTAN (PTDC/CTM-BIO/4388/2014), funded through the PIDDAC Program. A.C. and C.C. were supported by NORTE 2020, under the Portugal 2020 Partnership Agreement, through the ERDF (NORTE-01-0145-FEDER-000013), and by FCT (IF/00735/2014 and SFRH/BPD/96176/2013). G.S.D. and J.L.F. were supported by NIH grant AI-106269. K.J.K-C is supported by the Division of Intramural Research (DIR), NIAID, NIH.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Microbiol. 2018 Jul;3(7):791-803pt_PT
dc.identifier.doi10.1038/s41564-018-0167-xpt_PT
dc.identifier.eissn2058-5276
dc.identifier.urihttp://hdl.handle.net/10451/55246
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationANR-10-BLAN-1309pt_PT
dc.relationFungi in the setting of inflammation, allergy and autoimmune diseases:Translating basic science into clinical practices
dc.relationNORTE-01-0145-FEDER-000013pt_PT
dc.relationPreclinical Validation of a TNF-Capturing Device as Therapeutics of Inflammatory Arthritic Diseases.
dc.relationTHE ROLE OF INFLAMMASOME ACTIVATION IN HOST IMMUNITY TO FUNGAL INFECTION - The inflammasome-microbiota interplay in antifungal immunity
dc.relation.publisherversionhttps://www.nature.com/nmicrobiol/pt_PT
dc.titleCalcium sequestration by fungal melanin inhibits calcium–calmodulin signalling to prevent LC3-associated phagocytosispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleFungi in the setting of inflammation, allergy and autoimmune diseases:Translating basic science into clinical practices
oaire.awardTitlePreclinical Validation of a TNF-Capturing Device as Therapeutics of Inflammatory Arthritic Diseases.
oaire.awardTitleTHE ROLE OF INFLAMMASOME ACTIVATION IN HOST IMMUNITY TO FUNGAL INFECTION - The inflammasome-microbiota interplay in antifungal immunity
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/260338/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FCTM-BIO%2F4388%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00735%2F2014%2FCP1212%2FCT0001/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F96176%2F2013/PT
oaire.citation.endPage803pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage791pt_PT
oaire.citation.titleNature Microbiologypt_PT
oaire.citation.volume3pt_PT
oaire.fundingStreamFP7
oaire.fundingStream3599-PPCDT
oaire.fundingStreamInvestigador FCT
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/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscoveryafb302b1-8272-48de-b347-cb5b54a0a3da
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