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Cited by 175Cell death mechanisms and regulationFerroptosis and cancer prognosisNF-κB Signaling Pathways

MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

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Dovey, Cole M., Diep, Jonathan, Clarke, Bradley P., Hale, Andrew T., McNamara, Dan E., Guo, Hongyan, Brown, Nathaniel W., Cao, Jennifer Yinuo +10 more·2018·Molecular Cell
DOI 10.1016/j.molcel.2018.05.010PMC PMC5994928
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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.

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Authors
Dovey, C. M., Diep, J., Clarke, B. P., Hale, A. T., McNamara, D. E., Guo, H., Brown, N. W., Cao, J. Y., Grace, C. R., Gough, P. J., Bertin, J., Dixon, S. J., Fiedler, D., Mocarski, E. S., Kaiser, W. J., Moldoveanu, T., York, J. D., & Carette, J. E.
Affiliations
  • Stanford Medicine (US)
  • Vanderbilt University (US)
  • St. Jude Children's Research Hospital (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Princeton University (US)
  • Stanford University (US)
  • GlaxoSmithKline (United States) (US)
  • Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
  • Emory University (US)
Corresponding author
Carette, Jan E.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2018-06
Volume
70
Issue
5
Pages
936-948.e7
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2018.05.010
PMC
PMC5994928
OpenAlex
W2805282583
Cited by
175
References
4
Citations by year
2026: 12 · 2025: 20 · 2024: 21 · 2023: 17 · 2022: 26 · 2021: 24 · 2020: 23 · 2019: 25 · 2018: 6
FWCI
6.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (T32AI007328, DP2AI104557, 5T32GM007347, R01AI020211, R01GM124404)
  • The David and Lucile Packard Foundation
  • St. Jude Academic Programs Office Special Postdoctoral Fellowship
  • ALSAC
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
necroptosis, MLKL, inositol polyphosphate multikinase, regulated cell death, RIPK3, herpesvirus infection, cell death signaling
MeSH terms
Binding Sites, Colonic Neoplasms, Humans, Inositol Phosphates, Mutation, Phosphorylation, Protein Kinases, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Cell Death, Phosphotransferases (Alcohol Group Acceptor), Herpesvirus 1, Human, HT29 Cells, Jurkat Cells, Receptor-Interacting Protein Serine-Threonine Kinases

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