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dc.contributor.authorGarcia, LR
dc.contributor.authorTenev, T
dc.contributor.authorNewman, R
dc.contributor.authorHaich, RO
dc.contributor.authorLiccardi, G
dc.contributor.authorJohn, SW
dc.contributor.authorAnnibaldi, A
dc.contributor.authorYu, L
dc.contributor.authorPardo, M
dc.contributor.authorYoung, SN
dc.contributor.authorFitzgibbon, C
dc.contributor.authorFernando, W
dc.contributor.authorGuppy, N
dc.contributor.authorKim, H
dc.contributor.authorLiang, L-Y
dc.contributor.authorLucet, IS
dc.contributor.authorKueh, A
dc.contributor.authorRoxanis, I
dc.contributor.authorGazinska, P
dc.contributor.authorSims, M
dc.contributor.authorSmyth, T
dc.contributor.authorWard, G
dc.contributor.authorBertin, J
dc.contributor.authorBeal, AM
dc.contributor.authorGeddes, B
dc.contributor.authorChoudhary, JS
dc.contributor.authorMurphy, JM
dc.contributor.authorAurelia Ball, K
dc.contributor.authorUpton, JW
dc.contributor.authorMeier, P
dc.date.accessioned2021-08-13T08:20:28Z
dc.date.available2021-08-13T08:20:28Z
dc.date.issued2021-06-07
dc.identifier.citationNature communications, 2021, 12 (1), pp. 3364 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4763
dc.identifier.eissn2041-1723
dc.identifier.eissn2041-1723en_US
dc.identifier.doi10.1038/s41467-021-23474-5
dc.identifier.doi10.1038/s41467-021-23474-5en_US
dc.description.abstractNecroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
dc.formatElectronic
dc.format.extent3364 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCells, Cultured
dc.subjectCell Line
dc.subjectHT29 Cells
dc.subjectNIH 3T3 Cells
dc.subjectSkin
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectMuromegalovirus
dc.subjectHerpesviridae Infections
dc.subjectNecrosis
dc.subjectProtein Kinases
dc.subjectLysine
dc.subjectUbiquitination
dc.subjectHEK293 Cells
dc.subjectNecroptosis
dc.titleUbiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.
dc.typeJournal Article
dcterms.dateAccepted2021-04-29
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-23474-5
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-06-07
rioxxterms.licenseref.startdate2021-06-07en_US
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/ImmNet
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Cell Death and Immunity
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group
pubs.organisational-group/ICR
pubs.organisational-group/ICR/ImmNet
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Cell Death and Immunity
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group
pubs.publication-statusPublished
pubs.volume12en_US
pubs.embargo.termsNot known
icr.researchteamCell Death and Immunity
icr.researchteamFunctional Proteomics Group
icr.researchteamCell Death and Immunityen_US
icr.researchteamFunctional Proteomics Groupen_US
dc.contributor.icrauthorPardo Calvo, Maria Mercedesen
dc.contributor.icrauthorMeier, Pascalen
dc.contributor.icrauthorChoudhary, Jyotien


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