MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.
Journal Article (Journal Article)
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Full Text
Duke Authors
Cited Authors
- Dovey, CM; Diep, J; Clarke, BP; Hale, AT; McNamara, DE; Guo, H; Brown, NW; Cao, JY; Grace, CR; Gough, PJ; Bertin, J; Dixon, SJ; Fiedler, D; Mocarski, ES; Kaiser, WJ; Moldoveanu, T; York, JD; Carette, JE
Published Date
- June 7, 2018
Published In
Volume / Issue
- 70 / 5
Start / End Page
- 936 - 948.e7
PubMed ID
- 29883610
Pubmed Central ID
- PMC5994928
Electronic International Standard Serial Number (EISSN)
- 1097-4164
Digital Object Identifier (DOI)
- 10.1016/j.molcel.2018.05.010
Language
- eng
Conference Location
- United States