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Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis.
- Source :
-
The EMBO journal [EMBO J] 2021 Dec 01; Vol. 40 (23), pp. e103718. Date of Electronic Publication: 2021 Oct 26. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021 The Authors.)
- Subjects :
- Animals
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Proteasome Endopeptidase Complex
Protein Kinases chemistry
Protein Kinases genetics
Ubiquitin Thiolesterase genetics
Cell Membrane metabolism
Necroptosis
Protein Kinases metabolism
Protein Kinases physiology
Protein Multimerization
Ubiquitin Thiolesterase metabolism
Ubiquitination
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 40
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 34698396
- Full Text :
- https://doi.org/10.15252/embj.2019103718