MLKL Requires the Inositol Phosphate Code to Execute Necroptosis

• Type of Material: Article
• Authors: Cole M. Dovey, Stanford University; Jonathan Diep, Stanford University; Bradley P. Clarke, Vanderbilt University; Andrew T. Hale, Vanderbilt University; Dan E. McNamara, St. Jude Children's Research Hospital; Hongyan Guo, University of Texas Health Sciences Center, San Antonio; Nathaniel W. Brown, Princeton University; Jennifer Yinuo Cao, Stanford University; Christy R. Grace, St. Jude Children's Research Hospital; Peter J. Gough, GlaxoSmithKline; John Bertin, GlaxoSmithKline; Scott J. Dixon, Stanford University; Dorothea Fiedler, Leibniz-Forschungsinstitut für Molekulare Pharmakologie; Edward S Mocarski, Emory University; William J. Kaiser, University of Texas Health Sciences Center, San Antonio; Tudor Moldoveanu, St. Jude Children's Research Hospital; John D. York, Vanderbilt University; Jan E. Carette, Stanford University
• Language: English
• Date: 2018-06-07
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2018.05.010
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 70
• Issue: 5
• Start Page: 936
• End Page: +
• Grant/Funding Information: This work was supported in part by grants from the NIH: T32AI007328 (C.M.D.), DP2AI104557 (J.E.C.), 5T32GM007347 (A.T.H.), R01AI020211 (to E.S.M.), 1R01GM122923 (to S.J.D.), and R01GM124404 (to J.D.Y.).; Further support was provided by The David and Lucile Packard Foundation (J.E.C.); by the St. Jude Academic Programs Office Special Postdoctoral Fellowship (D.E.M.); and American Lebanese Syrian Associated Charities (T.M.).
• Keywords: HUMAN-CELLS; PROTEIN; MIXED LINEAGE KINASE; Life Sciences & Biomedicine; HOST FACTORS; BINDING; DOMAIN-LIKE; Science & Technology; NECROSIS; Biochemistry & Molecular Biology; Cell Biology; ACTIVATION; POLYPHOSPHATE MULTIKINASE; RIP3
• Research Categories: Health Sciences, Immunology; Chemistry, Biochemistry; Biology, Cell

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.