Ceramides bind VDAC2 to trigger mitochondrial apoptosis

DC FieldValueLanguage
dc.contributor.authorDadsena, Shashank
dc.contributor.authorBockelmann, Svenja
dc.contributor.authorMina, John G. M.
dc.contributor.authorHassan, Dina G.
dc.contributor.authorKorneev, Sergei
dc.contributor.authorRazzera, Guilherme
dc.contributor.authorJahn, Helene
dc.contributor.authorNiekamp, Patrick
dc.contributor.authorMueller, Dagmar
dc.contributor.authorSchneider, Markus
dc.contributor.authorTafesse, Fikadu G.
dc.contributor.authorMarrink, Siewert J.
dc.contributor.authorMelo, Manuel N.
dc.contributor.authorHolthuis, Joost C. M.
dc.date.accessioned2021-12-23T16:23:47Z-
dc.date.available2021-12-23T16:23:47Z-
dc.date.issued2019
dc.identifier.issn20411723
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/14662-
dc.description.abstractCeramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.
dc.description.sponsorshipDeutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB944-P14, HO3539/1-1]; Marie Curie Intra-European FellowshipEuropean Commission [289278]; German Egyptian Research Long-term Scholarship [57222240]; FEDER funds through COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI) [LISBOA-01-0145-FEDER-007660]; FCT-Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R21AI124225-01A1]; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R21AI124225] Funding Source: NIH RePORTER; This work was supported by the Deutsche Forschungsgemeinschaft (Projects SFB944-P14 and HO3539/1-1) to J.C.M.H., a Marie Curie Intra-European Fellowship to J.G.M.M. (Project 289278), and a German Egyptian Research Long-term Scholarship to D.G.H. (Project 57222240). M.N.M was supported by Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by FEDER funds through COMPETE2020-Programa Operacional Competitividade e Internacionalizacao (POCI) and by national funds through FCT-Fundacao para a Ciencia e a Tecnologia. M.N.M. and G.R. acknowledge the National Laboratory for Scientific Computing (LNCC/MCTI, Brazil) for providing HPC resources of the SDumont supercomputer (http://sdumont.lncc.br).Additional support was provided by the NIH (Project 1R21AI124225-01A1) to F.G.T.
dc.language.isoen
dc.publisherNATURE PUBLISHING GROUP
dc.relation.ispartofNATURE COMMUNICATIONS
dc.subjectBAX
dc.subjectCELL-DEATH
dc.subjectDEPENDENT ANION CHANNEL-1
dc.subjectEFFICIENT
dc.subjectINHIBITION
dc.subjectMEMBRANE
dc.subjectMultidisciplinary Sciences
dc.subjectPROTEINS
dc.subjectRADIATION-INDUCED APOPTOSIS
dc.subjectScience & Technology - Other Topics
dc.subjectSPHINGOLIPID METABOLISM
dc.subjectTRANSPORT
dc.titleCeramides bind VDAC2 to trigger mitochondrial apoptosis
dc.typejournal article
dc.identifier.doi10.1038/s41467-019-09654-4
dc.identifier.isiISI:000465200000013
dc.description.volume10
dc.contributor.orcid0000-0001-8423-5277
dc.contributor.orcid0000-0003-0429-1370
dc.contributor.orcid0000-0001-6567-0513
dc.contributor.orcid0000-0002-2754-015X
dc.contributor.orcid0000-0002-0227-5900
dc.contributor.orcid0000-0002-8575-4164
dc.contributor.orcid0000-0001-8912-1586
dc.contributor.researcheridG-3706-2014
dc.contributor.researcheridN-8622-2014
dc.contributor.researcheridAAL-9157-2020
dc.contributor.researcheridAAX-9374-2021
dc.contributor.researcheridW-7033-2019
dc.contributor.researcheridAAG-2675-2021
dc.publisher.placeMACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
dcterms.isPartOf.abbreviationNat. Commun.
dcterms.oaStatusGreen Published, gold
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptidfb05-
crisitem.author.deptidfb05-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidBoSv426-
crisitem.author.netidKoSe681-
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