MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

Cole M. Dovey, Jonathan Diep, Bradley P. Clarke, Andrew T. Hale, Dan E. McNamara, Hongyan Guo, Nathaniel W. Brown, Jennifer Yinuo Cao, Christy R. Grace, Peter J. Gough, John Bertin, Scott J. Dixon, Dorothea Fiedler, Edward S. Mocarski, William J. Kaiser, Tudor Moldoveanu, John D. York, Jan E. Carette

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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. Dovey et al. report an unexpected layer of regulation governing a form of cell death termed necroptosis. They find that the inositol phosphate code controls the executioner protein MLKL to induce cell lysis. This study deepens our understanding of cell death mechanisms important for infection, inflammation, and cancer.

Original languageEnglish (US)
Pages (from-to)936-948.e7
JournalMolecular Cell
Volume70
Issue number5
DOIs
StatePublished - Jun 7 2018

Keywords

  • IP kinase
  • IPMK
  • ITPK1
  • MLKL
  • RIPK3
  • cell death
  • inositol phosphate
  • necroptosis
  • proinflammatory cytokine
  • regulated necrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'MLKL Requires the Inositol Phosphate Code to Execute Necroptosis'. Together they form a unique fingerprint.

Cite this