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Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis.
- Source :
-
Nature cell biology [Nat Cell Biol] 2014 Jan; Vol. 16 (1), pp. 55-65. Date of Electronic Publication: 2013 Dec 08. - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Animals
Calcium metabolism
Cell Membrane drug effects
HEK293 Cells
HT29 Cells
Humans
Imidazoles pharmacology
Indoles pharmacology
Jurkat Cells
Mice
Mutant Proteins chemistry
Mutant Proteins metabolism
Protein Kinases chemistry
Protein Serine-Threonine Kinases
Protein Structure, Tertiary
Protein Transport drug effects
RNA, Small Interfering metabolism
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
TRPM Cation Channels metabolism
Apoptosis drug effects
Cell Membrane metabolism
Necrosis pathology
Protein Kinases metabolism
Protein Multimerization drug effects
Tumor Necrosis Factor-alpha pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4679
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 24316671
- Full Text :
- https://doi.org/10.1038/ncb2883