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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.accessioned2020-11-19T05:05:32Z
dc.date.available2020-11-19T05:05:32Z
dc.date.issued2020-11-02
dc.date.submitted2020-01-28
dc.identifier.other55547
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/313087
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.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectCell Biology
dc.subjectImmunology and Inflammation
dc.subjectWiskott Aldrich syndrome
dc.subjectactin cytoskeleton
dc.subjectimmunometabolism
dc.subjectautophagy
dc.subjectinnate immune cells
dc.subjectHuman
dc.subjectMouse
dc.titleWiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells
dc.typeArticle
dc.date.updated2020-11-19T05:05:31Z
prism.publicationNameeLife
prism.volume9
dc.identifier.doi10.17863/CAM.60187
dcterms.dateAccepted2020-10-31
rioxxterms.versionofrecord10.7554/elife.55547
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Horng, Tiffany
datacite.contributor.supervisorsenior_editor: Taniguchi, Tadatsugu
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
pubs.funder-project-idWellcome Trust (090233/Z/09/Z)
pubs.funder-project-idWellcome Trust (201250/Z/16/Z)
pubs.funder-project-idNational Institute for Health Research (Great Ormond Street Hospital for Children NHS Foundation Trust)


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