MLKL, the Protein that Mediates Necroptosis, Also Regulates Endosomal Trafficking and Extracellular Vesicle Generation
Open accessAbstract
Activation of the pseudokinase mixed lineage kinase domain-like (MLKL) upon its phosphorylation by the protein kinase RIPK3 triggers necroptosis, a form of programmed cell death in which rupture of cellular membranes yields release of intracellular components. We report that MLKL also associated with endosomes and controlled the transport of endocytosed proteins, thereby enhancing degradation of receptors and ligands, modulating their induced signaling and facilitating the generation of extracellular vesicles. This role was exerted on two quantitative grades: a constitutive one independent of RIPK3, and an enhanced one, triggered by RIPK3, where the association of MLKL with the endosomes was enhanced, and it was found to bind endosomal sorting complexes required for transport (ESCRT) proteins and the flotillins and to be excluded, together with them, from cells within vesicles. We suggest that release of phosphorylated MLKL within extracellular vesicles serves as a mechanism for self-restricting the necroptotic activity of this protein.
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Formation of PS-exposing plasma membrane bubbles whose breakdown and release is negatively regulated-in conditions of limited MLKL activation-by ESCRT-III machinery.
“This is followed by the formation of PS-exposing plasma membrane bubbles whose breakdown and release is negatively regulated—in conditions of limited MLKL activation—by the antagonistic activity of the endosomal sorting complex required for transport (ESCRT)-III machinery [456, 457].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [457]
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- Authors
- Yoon, S., Kovalenko, A., Bogdanov, K., & Wallach, D.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Wallach, David
- ORCID
- Wallach, David
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 47
- Issue
- 1
- Pages
- 51-65.e7
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2724720631
- Cited by
- 368
- References
- 5
- Citations by year
- 2026: 26 · 2025: 30 · 2024: 40 · 2023: 43 · 2022: 45 · 2021: 62 · 2020: 50 · 2019: 40 · 2018: 28 · 2017: 4
- FWCI
- 13.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- MLKL, necroptosis, RIPK3, endosomal trafficking, extracellular vesicles, ESCRT proteins, flotillin, receptor degradation, programmed cell death, membrane rupture
- MeSH terms
- Extracellular Vesicles, Cell Line, Humans, Mutation, Necrosis, Phosphorylation, Protein Kinases, Endosomes, Protein Engineering, Signal Transduction, Apoptosis, Protein Transport, RNA, Small Interfering, Proteomics, Receptor-Interacting Protein Serine-Threonine Kinases
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