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dc.contributor.authorRivers, Elizabeth
dc.contributor.authorRai, Rajeev
dc.contributor.authorLötscher, Jonas
dc.contributor.authorHollinshead, Michael
dc.contributor.authorMarkelj, Gasper
dc.contributor.authorThaventhiran, James
dc.contributor.authorWorth, Austen
dc.contributor.authorCavazza, Alessia
dc.contributor.authorHess, Christoph
dc.contributor.authorBajaj-Elliott, Mona
dc.contributor.authorThrasher, Adrian J
dc.date.accessioned2021-02-02T00:30:26Z
dc.date.available2021-02-02T00:30:26Z
dc.date.issued2020-11-02
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/316944
dc.description.abstractThe actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
dc.format.mediumElectronic
dc.languageeng
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line
dc.subjectMitochondria
dc.subjectMacrophages
dc.subjectHumans
dc.subjectGene Expression Regulation
dc.subjectHomeostasis
dc.subjectAutophagy
dc.subjectWiskott-Aldrich Syndrome Protein
dc.titleWiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells.
dc.typeArticle
prism.publicationDate2020
prism.publicationNameElife
prism.volume9
dc.identifier.doi10.17863/CAM.64056
dcterms.dateAccepted2020-10-31
rioxxterms.versionofrecord10.7554/eLife.55547
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-11-02
dc.contributor.orcidRivers, Elizabeth [0000-0001-5814-8014]
dc.contributor.orcidWorth, Austen [0000-0001-6803-7385]
dc.contributor.orcidThrasher, Adrian J [0000-0002-6097-6115]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Review
cam.issuedOnline2020-11-02


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