Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis
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The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.
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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 [449]
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- Authors
- Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.-C., Choksi, S., Liu, J., Ward, Y., Wu, L.-G., & Liu, Z.-G.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Liu, Zheng-Gang
- Venue
- Nature Cell Biology
- Published
- 2013-12-08
- Volume
- 16
- Issue
- 1
- Pages
- 55-65
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC8369836
- OpenAlex
- W2091363184
- Cited by
- 1,322
- References
- 33
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- FWCI
- 36.82
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-01-31)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010783, ZIASC010376)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- MLKL, necroptosis, TNF signaling, RIPK3, plasma membrane translocation, protein trimerization, coiled-coil domain, calcium influx, TRPM7, necrosome
- MeSH terms
- Animals, Calcium, Cell Membrane, Humans, Imidazoles, Indoles, Necrosis, Protein Kinases, Tumor Necrosis Factor-alpha, Apoptosis, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, HT29 Cells, Jurkat Cells, Protein Transport, RNA, Small Interfering, TRPM Cation Channels, Mutant Proteins, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Protein Multimerization, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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