Garcia, Laura Ramos, Tenev, Tencho, Newman, Richard, Haich, Rachel O., Liccardi, Gianmaria, John, Sidonie Wicky, Annibaldi, Alessandro, Yu, Lu, Pardo, Mercedes ORCID: 0000-0002-3477-9695, Young, Samuel N., Fitzgibbon, Cheree, Fernando, Winnie, Guppy, Naomi, Kim, Hyojin, Liang, Lung-Yu, Lucet, Isabelle S., Kueh, Andrew, Roxanis, Ioannis, Gazinska, Patrycja, Sims, Martin, Smyth, Tomoko, Ward, George, Bertin, John, Beal, Allison M., Geddes, Brad, Choudhary, Jyoti S., Murphy, James M., Ball, K. Aurelia, Upton, Jason W. and Meier, Pascal (2021). Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity. Necroptosis 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Garcia, Laura RamosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tenev, TenchoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newman, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haich, Rachel O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liccardi, GianmariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Sidonie WickyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Annibaldi, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, LuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pardo, MercedesUNSPECIFIEDorcid.org/0000-0002-3477-9695UNSPECIFIED
Young, Samuel N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fitzgibbon, ChereeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernando, WinnieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guppy, NaomiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, HyojinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liang, Lung-YuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucet, Isabelle S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kueh, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roxanis, IoannisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gazinska, PatrycjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sims, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smyth, TomokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ward, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertin, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beal, Allison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geddes, BradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choudhary, Jyoti S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murphy, James M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ball, K. AureliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Upton, Jason W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-600587
DOI: 10.1038/s41467-021-23474-5
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MIXED LINEAGE KINASE; DOMAIN-LIKE PROTEIN; MEDIATES NECROPTOSIS; FORCE-FIELDS; CELL-DEATH; BINDING; RIPK1; ACTIVATION; APOPTOSIS; NECROSISMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60058

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