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MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.

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
Mol Cell. 2018 70 (5): 936-948.e7

PMID: 29883610 · PMCID: PMC5994928 · DOI:10.1016/j.molcel.2018.05.010

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.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (17)

Binding Sites Cell Death Colonic Neoplasms Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Herpesvirus 1, Human HT29 Cells Humans Inositol Phosphates Jurkat Cells Mutation Phosphorylation Phosphotransferases (Alcohol Group Acceptor) Protein Kinases Receptor-Interacting Protein Serine-Threonine Kinases Signal Transduction Tumor Necrosis Factor-alpha

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