Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL

• Type of Material: Article
• Authors: William Kaiser, Emory University; Haripriya Sridharan, University of Texas Austin; Chunzi Huang, Emory University; Pratyusha Mandal, Emory University; Jason W. Upton, University of Texas Austin; Peter J. Gough, GlaxoSmithKline; Clark A. Sehon, GlaxoSmithKline; Robert W. Marquis, GlaxoSmithKline; John Bertin, GlaxoSmithKline; Edward S Mocarski, Emory University
• Language: English
• Date: 2013-10-25
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M113.462341
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 288
• Issue: 43
• Start Page: 31268
• End Page: 31279
• Grant/Funding Information: This work was also supported by funds from the University of Texas at Austin, the Cancer Prevention Research Institute of Texas (to J. W. U.), and by GlaxoSmithKline (to P. J. G., C. A. S., R. W. M., and J. B.).; This work was supported, in whole or in part, by National Institutes of Health Grants RO1 AI030363 and AI020211, Pilot Grant UL1 RR025008 from ACTSI (to E. S. M.), and OD012198 (to W. J. K.).
• Keywords: DOMAIN-LIKE; Life Sciences & Biomedicine; NF-KAPPA-B; MIXED LINEAGE KINASE; TNF-INDUCED NECROSIS; PROGRAMMED NECROSIS; Biochemistry & Molecular Biology; Science & Technology; CELL-DEATH PATHWAY; INTERACTING PROTEIN; INDUCED APOPTOSIS; ADAPTER TRIF; HOMOTYPIC INTERACTION MOTIF
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-κB together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-β (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction motif-dependent association of TRIF with RIP3 kinase (also called RIPK3). In fibroblasts, this pathway proceeds independent of RIP1 or its kinase activity, but it remains dependent on mixed lineage kinase domain-like protein (MLKL) downstream of RIP3 kinase. Here, we describe two small molecule RIP3 kinase inhibitors and employ them to demonstrate the common requirement for RIP3 kinase in programmed necrosis induced by RIP1-RIP3, DAI-RIP3, and TRIF-RIP3 complexes. Cell fate decisions following TLR signaling parallel death receptor signaling and rely on caspase 8 to suppress RIP3-dependent programmed necrosis whether initiated directly by a TRIF-RIP3-MLKL pathway or indirectly via TNF activation and the RIP1-RIP3-MLKL necroptosis pathway.