title: Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.
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.
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.forename: Haripriya
authors.initials: H
authors.lastname: Sridharan
authors.forename: Chunzi
authors.initials: C
authors.lastname: Huang
authors.forename: Pratyusha
authors.initials: P
authors.lastname: Mandal
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D006023:Glycoproteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C402632:Zbp1 protein, mouse; C570694:MLKL protein, mouse; C485615:Ripk3 protein, mouse
keywords: Apoptosis; Caspase; Necrosis (Necrotic Death); RIPK3; Serine/Threonine Protein Kinase; Toll-like Receptors (TLR)
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