MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.

Published

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

  • 29883610

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2018.05.010

Language

  • eng