True Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity This information is current as Edward S. Mocarski, William J. Kaiser, Devon of September 23, 2021. Livingston-Rosanoff, Jason W. Upton and Lisa P. Daley-Bauer J Immunol 2014; 192:2019-2026; ; doi: 10.4049/jimmunol.1302426 http://www.jimmunol.org/content/192/5/2019 Downloaded from References This article cites 119 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/192/5/2019.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology True Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity Edward S. Mocarski,*,† William J. Kaiser,*,† Devon Livingston-Rosanoff,*,† Jason W. Upton,‡ and Lisa P. Daley-Bauer*,† Programmed necrosis mediated by receptor interacting bris to promote Ag cross-presentation by dendritic cells (DCs), protein kinase (RIP)3 (also called RIPK3) has emerged thereby supporting a robust adaptive immune response that as an alternate death pathway triggered by TNF family ultimately controls infection. The study of virus-encoded cell death receptors, pathogen sensors, IFNRs, Ag-specific death suppressor mutants brought RIP3 necrosis to light, re- TCR activation, and genotoxic stress. Necrosis leads vealing interdependencies fostered by a pathogen–host arms to cell leakage and acts as a “trap door,” eliminating cells race centered on cell death measures and countermeasures (5). that cannot die by apoptosis because of the elaboration of Based on the variety of strategies that have been observed, cell Downloaded from pathogen-encoded caspase inhibitors. Necrotic signaling death suppressors are crucial to the pathogenesis of all large requires RIP3 binding to one of three partners—RIP1, DNA viruses (2, 3, 5, 8, 9). Because cell death is triggered by DAI, or TRIF—via a common RIP homotypic inter- pre-existing cellular machinery, dysregulation can inadvertently action motif. Once activated, RIP3 kinase targets the kill cells and cause inflammatory disease, even in the absence of infection (7). The distribution of these pathways in all somatic pseudokinase mixed lineage kinase domain-like to drive http://www.jimmunol.org/ cells opens possible routes to improve host resistance to natural cell lysis. Although necrotic and apoptotic death can pathogens, as well as to prevent infection of novel biothreat enhance T cell cross-priming during infection, mice agents. This review provides a perspective on recent advances in that lack these extrinsic programmed cell death path- RIP3 necrosis. The intention is to highlight triggers and al- ways are able to produce Ag-specific T cells and control ternate pathways of extrinsic cell death where therapeutic in- viral infection. The entwined relationship of apoptosis tervention might improve innate resistance to infection or drive and necrosis evolved in response to pathogen-encoded better cross-presentation during vaccination, without risking suppressors to support host defense and contribute to increased inflammatory disease (10). The derivation of viable, inflammation. The Journal of Immunology,2014,192: fertile, and immunocompetent mice with combined deficiency by guest on September 23, 2021 2019–2026. in Casp8 and RIP3 (11) dismisses any key role for Casp8- regulated pathways in development, but it certainly raises im- egulated cell death is a potent arm of host defense (1– portant questions as to how apoptosis, as well as necrosis, con- 4), involving alternate strategies that evolved with tributes to the function of the immune system. animals to counteract pathogen-encoded cell death R Alternate Casp8-apoptosis and RIP3-necrosis pathways suppressors (3, 5). Intrinsic (mitochondrial) apoptosis is nec- essary for development (6), whereas extrinsic apoptosis and To set the stage for discussing the current understanding of programmed necrosis play out as alternate innate immune RIP3 kinase in host defense, it is important to consider the countermeasures to control infection (3, 5, 7). Although mech- crucial role that TNF-mediated signal transduction has played anistically distinct from Casp8-mediated extrinsic apoptosis, re- in the elaboration of alternate cytoprotective and cytotoxic ceptor interacting protein kinase (RIP)3 necrosis similarly pathways (1, 12). Three distinct outcomes of signal transduc- eliminates infected cells prior to release of viral progeny, tion via the TNF death receptor, TNFR1, are recognized: cyto- halting infection and triggering an inflammatory response (7). kine activation, extrinsic apoptosis, and programmed necrosis. Importantly, extrinsic apoptosis and necrotic cell death ma- These converge on death domain (DD) signaling that is or- chinery is distributed in all somatic cells. These pathways chestrated via the adaptor FADD in complex with Casp8 and reduce the burden of infection while also producing cell de- specific inhibitor, FLIP (12, 13) (Fig. 1). Pathogen sensors, *Department of Microbiology and Immunology, Emory University School of Medicine, Emory University School of Medicine, Atlanta, GA 30322. E-mail address: mocarski@ Atlanta, GA 30322; †Emory Vaccine Center, Emory University School of Medicine, emory.edu Atlanta, GA 30322; and ‡Department of Molecular Biosciences, Institute for Cellular Abbreviations used in this article: DAI, DNA-dependent activator of IRF; DC, dendritic and Molecular Biology, University of Texas at Austin, Austin, TX 78712 cell; DD, death domain; DED, death effector domain; HCMV, human CMV; MCMV, Received for publication October 2, 2013. Accepted for publication December 20, 2013. murine CMV; MLKL, mixed lineage kinase domain-like; RHIM, receptor interacting protein kinase homotypic interaction motif; RIP, receptor interacting protein kinase; This work was supported by National Institutes of Health Grants R01 AI030363 vFLIP, viral FLIP; vICA, viral inhibitor of Casp8 activation; vIRA, viral inhibitor of and AI020211 to E.S.M., National Institutes of Health Grant T32GM008169 and receptor interacting protein kinase activation; WT, wild-type. an Achievement Rewards for College Scientists Fellowship to D.L.-R., National Insti- tutes of Health Grant OD012198 to W.J.K., and start-up funds from the University of Ó Texas at Austin and the Cancer Prevention Research Institute of Texas to J.W.U. Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Prof. Edward S. Mocarski, Department of Microbiology and Immunology, Emory Vaccine Center, 1462 Clifton Road NE, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302426 2020 BRIEF REVIEWS: IMMUNE IMPLICATIONS OF RIP3 NECROSIS IFNs, TCRs, and genotoxic stress all trigger analogous out- well as necroptosis, first emerged in studies of TNFR1 DD comes. Insights from TNFR DD signaling and identification signaling (22, 35, 36). Necroptosis is triggered when Casp8 of virus-encoded cell death suppressors using TNF-based becomes compromised during death signal transduction. In assays (14–16) has brought an appreciation of core cell these settings, RIP1 functions as both a RIP homotypic inter- death machinery operating as an integrated pathogen sensor action motif (RHIM)-dependent adaptor and a protein kinase system (5). In line with the view that extrinsic death came into to phosphorylate RIP3 (37–39), a partnership that results in existence to support host defense, both TNF antagonist im- formation of an amyloid-like complex (40). RIP3 kinase munotherapy (17) and genetic linkage studies (18) show that undergoes autophosphorylation and subsequently activates TNF signaling contributes as a redundant factor in host de- a target protein, mixed lineage kinase domain-like (MLKL), fense, like many other innate immune mechanisms. A goal of by phosphorylating key amino acids (7, 41, 42). The final steps this review is to highlight the growing evidence that TNF in this pathway involve the formation of an MLKL homotrimer opened the awareness to a broadly distributed innate cell that translocates to the plasma membrane to mediate Ca2+ influx death system able to prevent infection. via a transient receptor potential melastatin related 7 channel TNF family death receptors. TNFR1, as well as the Fas/CD95 (43). A similar RIP3–MLKL axis (28) is apparently shared by and TRAIL death receptors, control NF-kB activation, extrinsic the three pathways leading to RIP3 necrosis, whether RIP1 apoptosis, and programmed necrosis by DD signal transduction, dependent or RIP1 independent (Fig. 2). functioning in collaboration with death effector domain (DED) Pathogen sensors. Pathogen recognition receptors trigger