Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis.
DUB-fusion
MLKL
membranes
necroptosis
ubiquitylation
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
revised:
02
09
2021
received:
14
10
2019
accepted:
20
09
2021
pubmed:
27
10
2021
medline:
22
12
2021
entrez:
26
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34698396
doi: 10.15252/embj.2019103718
pmc: PMC8634140
doi:
Substances chimiques
USP21 protein, human
0
MLKL protein, human
EC 2.7.-
MLKL protein, mouse
EC 2.7.-
Protein Kinases
EC 2.7.-
Ubiquitin Thiolesterase
EC 3.4.19.12
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e103718Informations de copyright
© 2021 The Authors.
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