ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences
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The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca 2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
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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 [456]
MLKL oligomerization promotes cascade involving Ca2+ influx presumably mediated by TRPM7, and PS exposure directly operated by MLKL.
“Moreover, it has also been reported that MLKL oligomerization promotes a cascade of intracellular events involving (1) Ca2+ influx, which is presumably mediated by the MLKL target transient receptor potential cation channel subfamily M member 7 (TRPM7) [449]; and (2) PS exposure, which seems to be directly operated by MLKL [456].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [456]
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- Authors
- Gong, Y.-N., Guy, C., Olauson, H., Becker, J. U., Yang, M., Fitzgerald, P., Linkermann, A., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Karolinska Institutet (SE)
- University Hospital Cologne (DE)
- University Hospital Carl Gustav Carus (DE)
- Corresponding author
- Linkermann, Andreas
- Green, Douglas R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 169
- Issue
- 2
- Pages
- 286-300.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5443414
- OpenAlex
- W2604229956
- Cited by
- 689
- References
- 38
- Citations by year
- 2026: 66 · 2025: 65 · 2024: 60 · 2023: 71 · 2022: 83 · 2021: 109 · 2020: 82 · 2019: 63 · 2018: 59 · 2017: 29
- FWCI
- 26.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA169291, R01 AI44828)
- ALSAC
- Cluster of Excellence (EXC306)
- 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 › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- ESCRT-III, MLKL, RIPK3, necroptosis, regulated necrosis, plasma membrane integrity, phosphatidylserine exposure, calcium influx, cell survival, chemokine expression, programmed cell death
- MeSH terms
- Animals, Calcium, Cell Membrane, Cell Survival, Humans, Necrosis, Phosphatidylserines, Protein Kinases, Signal Transduction, HT29 Cells, Jurkat Cells, NIH 3T3 Cells, Mice, Endosomal Sorting Complexes Required for Transport
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