--Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy

DC FieldValueLanguage
dc.contributor.authorRamirez, Sabrina Chumpen
dc.contributor.authorGomez-Sanchez, Ruben
dc.contributor.authorVerlhac, Pauline
dc.contributor.authorHardenberg, Ralph
dc.contributor.authorMargheritis, Eleonora
dc.contributor.authorCosentino, Katia
dc.contributor.authorReggiori, Fulvio
dc.contributor.authorUngermann, Christian
dc.date.accessioned2023-02-17T11:35:27Z-
dc.date.available2023-02-17T11:35:27Z-
dc.date.issued2022
dc.identifier.issn1554-8627
dc.identifier.urihttp://osnascholar.ub.uni-osnabrueck.de/handle/unios/65510-
dc.description.abstractDuring macroautophagy/autophagy, precursor cisterna known as phagophores expand and sequester portions of the cytoplasm and/or organelles, and subsequently close resulting in double-membrane transport vesicles called autophagosomes. Autophagosomes fuse with lysosomes/vacuoles to allow the degradation and recycling of their cargoes. We previously showed that sequential binding of yeast Atg2 and Atg18 to Atg9, the only conserved transmembrane protein in autophagy, at the extremities of the phagophore mediates the establishment of membrane contact sites between the phagophore and the endoplasmic reticulum. As the Atg2-Atg18 complex transfers lipids between adjacent membranes in vitro, it has been postulated that this activity and the scramblase activity of the trimers formed by Atg9 are required for the phagophore expansion. Here, we present evidence that Atg9 indeed promotes Atg2-Atg18 complex-mediated lipid transfer in vitro, although this is not the only requirement for its function in vivo. In particular, we show that Atg9 function is dramatically compromised by a F627A mutation within the conserved interface between the transmembrane domains of the Atg9 monomers. Although Atg9(F627A) self-interacts and binds to the Atg2-Atg18 complex, the F627A mutation blocks the phagophore expansion and thus autophagy progression. This phenotype is conserved because the corresponding human ATG9A mutant severely impairs autophagy as well. Importantly, Atg9(F627A) has identical scramblase activity in vitro like Atg9, and as with the wild-type protein enhances Atg2-Atg18-mediated lipid transfer. Collectively, our data reveal that interactions of Atg9 trimers via their transmembrane segments play a key role in phagophore expansion beyond Atg9MODIFIER LETTER PRIMEs role as a lipid scramblase.
dc.description.sponsorshipHorizon 2020 [Marie Sklodowska Curie ETN] [765912]; Novo Nordisk Foundation [0066384]; ZonMW Top [91217002]; Deutsche Forschungsgemeinschaft [SFB 944, UN111/13-1]; Open Competition ENW-KLEIN [OCENW.KLEIN.118]; This work was supported by the Horizon 2020 [Marie Sklodowska Curie ETN (765912)]; Novo Nordisk Foundation [0066384]; ZonMW Top [91217002]; Deutsche Forschungsgemeinschaft; [SFB 944, P26] [UN111/13-1]; Open Competition ENW-KLEIN [OCENW.KLEIN.118].
dc.language.isoen
dc.publisherTAYLOR & FRANCIS INC
dc.relation.ispartofAUTOPHAGY
dc.subjectAutophagosome
dc.subjectBIOGENESIS
dc.subjectCell Biology
dc.subjectCOMPLEX
dc.subjectEARLY STEPS
dc.subjectlipid transfer
dc.subjectmembrane contact site
dc.subjectMITOCHONDRIA
dc.subjectphagophore
dc.subjectPROTEINS
dc.subjectRECRUITS ATG9
dc.subjectscramblase
dc.subjectSELECTIVE AUTOPHAGY
dc.subjectSITES
dc.subjectTRANSPORT
dc.subjectVESICLE FORMATION
dc.title--Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy
dc.typejournal article
dc.identifier.doi10.1080/15548627.2022.2136340
dc.identifier.isiISI:000881443400001
dc.contributor.orcid0000-0002-8274-3259
dc.contributor.orcid0000-0002-1059-4645
dc.contributor.orcid0000-0003-2652-2686
dc.contributor.researcheridI-4908-2014
dc.identifier.eissn1554-8635
dc.publisher.place530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
dcterms.isPartOf.abbreviationAutophagy
local.import.remainsaffiliations : University Osnabruck; University of Groningen; University Osnabruck; University Osnabruck; Aarhus University; Aarhus University
local.import.remainsearlyaccessdate : NOV 2022
local.import.remainsweb-of-science-index : Science Citation Index Expanded (SCI-EXPANDED)
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptidfb05-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidCoKa893-
crisitem.author.netidUnCh999-
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