ArticleThe EMBO journal2021
Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis.
Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 72 citations in OpenAlex.
- Ubiquitination and autophagy in host-pathogen interactions: from immune surveillance to therapeutic targeting.Nature reviews. Immunology · 2026Review
- Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.Nature communications · 2026Article
- Interconnected cell death pathways: central mechanisms and therapeutic targets in impaired follicular development of polycystic ovary syndrome.Journal of ovarian research · 2026Review
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- Remodeling the tumor immune microenvironment: mechanisms of crosstalk between regulated cell death macrophages.Frontiers in immunology · 2026Review
- Focus on necroptosis: its role in the pathogenesis and therapeutic potential of osteoarthritis.Frontiers in immunology · 2026Review
- The Interaction Between Ferroptosis and Necroptosis in Acute and Chronic Kidney Diseases.Journal of inflammation research · 2026Review
- MLKL/retromer axis controls PD-L1 recycling to compromise antitumor immunity during VCP inhibition-induced necroptosis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Neuronal Necroptosis Drives Neuroinflammation and Cognitive Decline Independent of Neuronal Cell Death.Aging and disease · 2025Article
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications.Journal of hematology & oncology · 2025Review
- The Role of Post-Translational Modifications in Necroptosis.Biomolecules · 2025Review
- The role of hydrogen sulfide in the regulation of necroptosis across various pathological processes.Molecular and cellular biochemistry · 2025Review
- Macrophage caspase-8 inhibition accelerates necrotic core expansion in atheroma plaque in mice.Frontiers in immunology · 2025Article
- Radiotherapy elicits immunogenic cell death and metabolic shifts in the tumor microenvironment: implications for immunotherapy.International journal of medical sciences · 2025Review
- Elucidating the dual roles of apoptosis and necroptosis in diabetic wound healing: implications for therapeutic intervention.Burns & trauma · 2025Review
- Genetically-stable engineered optogenetic gene switches modulate spatial cell morphogenesis in two- and three-dimensional tissue cultures.Nature communications · 2024Article
- Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.The Biochemical journal · 2024Article
- Targeting necroptosis: a promising avenue for respiratory disease treatment.Cell communication and signaling : CCS · 2024Review
- MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.Cell death and differentiation · 2024Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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