Article

Viral modulation of programmed necrosis

Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Current opinion in virology 06/2013; 3(3). DOI: 10.1016/j.coviro.2013.05.019
Source: PubMed

ABSTRACT Apoptosis and programmed necrosis balance each other as alternate first line host defense pathways against which viruses have evolved countermeasures. Intrinsic apoptosis, the critical programmed cell death pathway that removes excess cells during embryonic development and tissue homeostasis, follows a caspase cascade triggered at mitochondria and modulated by virus-encoded anti-apoptotic B cell leukemia (BCL)2-like suppressors. Extrinsic apoptosis controlled by caspase 8 arose during evolution to trigger executioner caspases directly, circumventing viral suppressors of intrinsic (mitochondrial) apoptosis and providing the selective pressure for viruses to acquire caspase 8 suppressors. Programmed necrosis likely evolved most recently as a 'trap door' adaptation to extrinsic apoptosis. Receptor interacting protein (RIP)3 kinase (also called RIPK3) becomes active when either caspase 8 activity or polyubiquitylation of RIP1 is compromised. This evolutionary dialog implicates caspase 8 as a 'supersensor' alternatively activating and suppressing cell death pathways.

1 Follower
 · 
116 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accepted Author Version. Not yet edited or proofed. Please see disclaimer on the article abstract page.
    04/2015; DOI:10.4161/23723556.2014.975093
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Herpesviruses suppress cell death to assure sustained infection in their natural hosts. Murine cytomegalovirus (MCMV) encodes suppressors of apoptosis as well as M45-encoded viral inhibitor of RIP activation (vIRA) to block RIP homotypic interaction motif (RHIM)-signaling and recruitment of RIP3 (also called RIPK3), to prevent necroptosis. MCMV and human cytomegalovirus encode a viral inhibitor of caspase (Casp)8 activation to block apoptosis, an activity that unleashes necroptosis. Herpes simplex virus (HSV)1 and HSV2 incorporate both RHIM and Casp8 suppression strategies within UL39-encoded ICP6 and ICP10, respectively, which are herpesvirus-conserved homologs of MCMV M45. Both HSV proteins sensitize human cells to necroptosis by blocking Casp8 activity while preventing RHIM-dependent RIP3 activation and death. In mouse cells, HSV1 ICP6 interacts with RIP3 and, surprisingly, drives necroptosis. Thus, herpesviruses have illuminated the contribution of necoptosis to host defense in the natural host as well as its potential to restrict cross-species infections in nonnatural hosts. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 03/2015; DOI:10.1016/j.virol.2015.03.016 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Receptor-interacting protein kinase 3, RIP3, and a pseudokinase mixed lineage kinase-domain like protein, MLKL, constitute the core components of the necroptosis pathway, which causes programmed necrotic death in mammalian cells. Latent RIP3 in the cytosol is activated by several upstream signals including the related kinase RIP1, which transduces signals from the tumor necrosis factor (TNF) family of cytokines. We report here that RIP3 activation following the induction of necroptosis requires the activity of an HSP90 and CDC37 cochaperone complex. This complex physically associates with RIP3. Chemical inhibitors of HSP90 efficiently block necroptosis by preventing RIP3 activation. Cells with knocked down CDC37 were unable to respond to necroptosis stimuli. Moreover, an HSP90 inhibitor that is currently under clinical development as a cancer therapy was able to prevent systemic inflammatory response syndrome in rats treated with TNF-α. HSP90 and CDC37 cochaperone complex-mediated protein folding is thus an important part of the RIP3 activation process during necroptosis. HSP90 | CDC37 | RIP3 | necrosis | kinase N ecroptosis is a form of necrotic cell death that is executed by a defined biochemical pathway. The key signaling molecule of this pathway is the protein kinase receptor interacting protein kinase 3 (RIP3) (1–3). RIP3 is expressed in a cell type-specific manner, with pronounced expression in hematopoietic cells including lymphocytes and macrophages, as well as in endothelial cells that line the gastric-intestinal tract (2). A variety of upstream signaling molecules have been shown to transduce signals to RIP3 to trigger necrosis. These include the close relative RIP1, which signals the activation of the tumor necrosis factor (TNF) family of cytokines; TRIF, which activates RIP3 upon the activation of toll-like receptors; and DAI, which causes necrosis upon viral infection (4, 5). All of these upstream proteins contain RIP homotypic interaction motif (RHIM) domains, through which they interact with a similar domain in RIP3. The activation of RIP3 is marked by the phosphorylation of the serine 227 site of human RIP3; this causes the formation of amyloid-like structures that can be observed as dots under a light microscope (6, 7). This serine phosphorylation is required for the interaction of RIP3 with its substrate MLKL (7). MLKL is a pseudokinase that contains an N-terminal helix bundle of four alpha-helixes that is connected to its C-terminal kinase-like domain through a two-helix linker (8). The protein typically exists in an inactive monomer form in live cells. Upon binding to RIP3 through its kinase-like domain, human MLKL is phosphorylated at two adjacent sites: threonine 357 and serine 358 (7). These phosphorylations drive MLKL toward an oligo-meric state that allows MLKL to translocate from the cytosol to the plasma and intracellular membranes by binding to phos-phoinositol phosphates and cardiolipin (9–13). The oligomer MLKL either directly disrupts membrane structures or indirectly damages membrane structures through calcium and/or sodium channel-mediated ion influxes, resulting in necrotic cell death. RIP3–MLKL-mediated cell death is an important component of antiviral responses of host animals (1, 4, 14, 15). This process can also be activated by the host immune system in response to tissue injury. Such a response may have detrimental effects to the host animal through secondary, immune-inflicted multitissue damage (4). Blocking necroptosis could therefore improve the outcome of diseases with such an element. For example, a lethal systematic inflammatory response syndrome induced by TNF-α injection could be mitigated when the animals are lacking such a response (16). Cellular kinases are often associated with heat shock proteins, a protein family that is elevated upon stresses (17). HSP90 and its cochaperones are such an important part of kinase activation that small molecule inhibitors have been developed to treat cancers in which the aberrant activation of kinases drives cancer cell growth. Inhibition of HSP90 in those cancer cells selectively drives the overexpressed or mutated active kinase toward degradation , thereby curbing cancer cell growth (18). Such strategies have been advanced in more than 60 clinical trials for a variety of cancer indications over the last 10 years. In the course of our research into necroptosis, we noticed that RIP3 kinase is normally associated with the HSP90–CDC37 cochaperone complex. In this report, we present biochemical and genetic evidence to support the assertion that this cochaperone complex is required for RIP3 activation and the induction of necroptosis. This finding should have significant implications for the ongoing clinical trials that are based on HSP90 inhibitors.
    Proceedings of the National Academy of Sciences 04/2015; 112(16). DOI:10.1073/pnas.1505244112 · 9.81 Impact Factor

Full-text

Download
49 Downloads
Available from
May 28, 2014