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Mol Cell. 2018 Jun 7;70(5):936-948.e7. doi: 10.1016/j.molcel.2018.05.010. Epub 2018 Jun 7.

MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.

Author information

1
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Sciences Center, San Antonio, TX 78229, USA.
5
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
6
Department of Biology, Stanford University, Stanford, CA 94305, USA.
7
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Host Defense Discovery Performance Unit, Infectious Diseases Therapy Area Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
9
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
10
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
11
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
12
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: carette@stanford.edu.

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.

KEYWORDS:

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

PMID:
29883610
PMCID:
PMC5994928
[Available on 2019-06-07]
DOI:
10.1016/j.molcel.2018.05.010

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