Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance

Laura Ramos Garcia (), Tencho Tenev, Richard Newman, Rachel O. Haich, Gianmaria Liccardi, Sidonie Wicky John, Alessandro Annibaldi, Lu Yu, Mercedes Pardo, Samuel N. Young, Cheree Fitzgibbon, Winnie Fernando, Naomi Guppy, Hyojin Kim, Lung-Yu Liang, Isabelle S. Lucet, Andrew Kueh, Ioannis Roxanis, Patrycja Gazinska, Martin Sims, Tomoko Smyth (), George Ward, John Bertin, Allison M. Beal, Brad Geddes, Jyoti S. Choudhary, James M. Murphy, K. Aurelia Ball, Jason W. Upton and Pascal Meier ()
Additional contact information
Laura Ramos Garcia: The Institute of Cancer Research
Tencho Tenev: The Institute of Cancer Research
Richard Newman: The Institute of Cancer Research
Rachel O. Haich: Auburn University
Gianmaria Liccardi: The Institute of Cancer Research
Sidonie Wicky John: The Institute of Cancer Research
Alessandro Annibaldi: The Institute of Cancer Research
Lu Yu: The Institute of Cancer Research
Mercedes Pardo: The Institute of Cancer Research
Samuel N. Young: Walter and Eliza Hall Institute of Medical Research
Cheree Fitzgibbon: Walter and Eliza Hall Institute of Medical Research
Winnie Fernando: The Institute of Cancer Research
Naomi Guppy: The Institute of Cancer Research
Hyojin Kim: The Institute of Cancer Research
Lung-Yu Liang: Walter and Eliza Hall Institute of Medical Research
Isabelle S. Lucet: Walter and Eliza Hall Institute of Medical Research
Andrew Kueh: Walter and Eliza Hall Institute of Medical Research
Ioannis Roxanis: The Institute of Cancer Research
Patrycja Gazinska: The Institute of Cancer Research
Martin Sims: Astex Pharmaceuticals
Tomoko Smyth: Astex Pharmaceuticals
George Ward: Astex Pharmaceuticals
John Bertin: GlaxoSmithKline
Allison M. Beal: GlaxoSmithKline
Brad Geddes: GlaxoSmithKline
Jyoti S. Choudhary: The Institute of Cancer Research
James M. Murphy: Walter and Eliza Hall Institute of Medical Research
K. Aurelia Ball: Skidmore College
Jason W. Upton: Auburn University
Pascal Meier: The Institute of Cancer Research

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23474-5

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DOI: 10.1038/s41467-021-23474-5

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