Oligomerization‐driven MLKL ubiquitylation antagonizes necroptosis

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  • Zikou Liu
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Laura F Dagley
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Kristy Shield‐Artin
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Samuel N Young
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Aleksandra Bankovacki
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Xiangyi Wang
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Michelle Tang
    The Florey Institute of Neuroscience and Mental Health Parkville VIC Australia
  • Jason Howitt
    The Florey Institute of Neuroscience and Mental Health Parkville VIC Australia
  • Che A Stafford
    Gene Centre and Department of Biochemistry Ludwig Maximilian University of Munich Munich Germany
  • Ueli Nachbur
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Cheree Fitzgibbon
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Sarah E Garnish
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Andrew I Webb
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • David Komander
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • James M Murphy
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • Joanne M Hildebrand
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia
  • John Silke
    The Walter and Eliza Hall Institute of Medical Research Parkville VIC Australia

Abstract

<jats:title>Abstract</jats:title><jats:p>Mixed lineage kinase domain‐like (MLKL) is the executioner in the caspase‐independent form of programmed cell death called necroptosis. Receptor‐interacting serine/threonine protein kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here, we show that necroptosis‐specific multi‐mono‐ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin‐insoluble cell fraction comprising organellar and plasma membranes and protein aggregates. Appearance of this ubiquitylated MLKL form can be reduced by expression of a plasma membrane‐located deubiquitylating enzyme. Oligomerization‐induced MLKL ubiquitylation occurs on at least four separate lysine residues and correlates with its proteasome‐ and lysosome‐dependent turnover. Using a MLKL‐DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licences MLKL auto‐activation independent of necroptosis signalling in mouse and human cells. Therefore, in addition to the role of ubiquitylation in the kinetic regulation of MLKL‐induced death following an exogenous necroptotic stimulus, it also contributes to restraining basal levels of activated MLKL to avoid unwanted cell death.</jats:p>

Journal

  • The EMBO Journal

    The EMBO Journal 40 (23), e103718-, 2021-10-26

    Springer Science and Business Media LLC

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