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

Author

Listed:
  • 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
    University of Cologne)

  • Sidonie Wicky John

    (The Institute of Cancer Research)

  • Alessandro Annibaldi

    (The Institute of Cancer Research
    Center for Molecular Medicine Cologne (CMMC))

  • 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
    University of Melbourne)

  • Isabelle S. Lucet

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • 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
    Immunology and Inflammation Research Therapeutic Area at Sanofi)

  • 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
    University of Melbourne)

  • K. Aurelia Ball

    (Skidmore College)

  • Jason W. Upton

    (Auburn University)

  • Pascal Meier

    (The Institute of Cancer Research)

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.

Suggested Citation

  • 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 & W, 2021. "Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23474-5
    DOI: 10.1038/s41467-021-23474-5
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