Show simple item record

dc.contributor.authorDavies, Alexandra
dc.contributor.authorItzhak, Daniel N
dc.contributor.authorEdgar, James
dc.contributor.authorArchuleta, Tara L
dc.contributor.authorHirst, Jennifer
dc.contributor.authorJackson, Lauren P
dc.contributor.authorRobinson, Margaret
dc.contributor.authorBorner, Georg HH
dc.date.accessioned2018-12-14T00:31:49Z
dc.date.available2018-12-14T00:31:49Z
dc.date.issued2018-09-27
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286934
dc.description.abstractAdaptor protein 4 (AP-4) is an ancient membrane trafficking complex, whose function has largely remained elusive. In humans, AP-4 deficiency causes a severe neurological disorder of unknown aetiology. We apply unbiased proteomic methods, including 'Dynamic Organellar Maps', to find proteins whose subcellular localisation depends on AP-4. We identify three transmembrane cargo proteins, ATG9A, SERINC1 and SERINC3, and two AP-4 accessory proteins, RUSC1 and RUSC2. We demonstrate that AP-4 deficiency causes missorting of ATG9A in diverse cell types, including patient-derived cells, as well as dysregulation of autophagy. RUSC2 facilitates the transport of AP-4-derived, ATG9A-positive vesicles from the trans-Golgi network to the cell periphery. These vesicles cluster in close association with autophagosomes, suggesting they are the "ATG9A reservoir" required for autophagosome biogenesis. Our study uncovers ATG9A trafficking as a ubiquitous function of the AP-4 pathway. Furthermore, it provides a potential molecular pathomechanism of AP-4 deficiency, through dysregulated spatial control of autophagy.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHela Cells
dc.subjectMicrotubules
dc.subjectPhagosomes
dc.subjectTransport Vesicles
dc.subjecttrans-Golgi Network
dc.subjectHumans
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectCarrier Proteins
dc.subjectMembrane Proteins
dc.subjectVesicular Transport Proteins
dc.subjectAdaptor Protein Complex 4
dc.subjectProteomics
dc.subjectProtein Binding
dc.subjectPhenotype
dc.subjectModels, Biological
dc.subjectAutophagy
dc.subjectAutophagy-Related Proteins
dc.titleAP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameNat Commun
prism.startingPage3958
prism.volume9
dc.identifier.doi10.17863/CAM.34243
dcterms.dateAccepted2018-08-17
rioxxterms.versionofrecord10.1038/s41467-018-06172-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09-27
dc.contributor.orcidDavies, Alexandra [0000-0002-1594-8780]
dc.contributor.orcidItzhak, Daniel N [0000-0002-4720-273X]
dc.contributor.orcidEdgar, James [0000-0001-7903-8199]
dc.contributor.orcidHirst, Jennifer [0000-0001-9063-8494]
dc.contributor.orcidJackson, Lauren P [0000-0002-3705-6126]
dc.contributor.orcidRobinson, Margaret [0000-0003-0631-0053]
dc.contributor.orcidBorner, Georg HH [0000-0002-3166-3435]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (086598/Z/08/Z)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
cam.issuedOnline2018-09-27


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International