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


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.

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Available from: Edward S Mocarski
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    • "The dialog between RIP3 and Casp8 represents a dé tente where the enzymatic activity of each sits in control cell fate, expanding the concept of pathogen supersensor as a trap set to eliminate infection (Kaiser et al., 2013b). It has long been appreciated that suppression of Casp8 opens the necroptotic trap door, leading to RIP3-MLKL oligomerization (Kaiser et al., 2013b). This study highlights not only Casp8 suppression of RIP3 kinase activity but also the remarkable capacity for RIP3 to function upstream of Casp8 to drive apoptosis. "

    Full-text · Article · Nov 2014
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    • "These observations suggest that necroptosis participates in the first-line defense of multicellular organisms against invading pathogens, in particular those that express caspase inhibitors [55]. As a matter of fact, necroptosis has been shown to be determinant for the control of vaccinia virus infection in mice [18], and the genome of some viruses (e.g., cytomegalovirus) codes for RIPK3 inhibitors [56] [57]. "
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    ABSTRACT: It is now clear that apoptosis does not constitute the sole genetically-encoded form of cell death. Rather, cells can spontaneously undertake or exogenously be driven into a cell death subroutine that manifests with necrotic features, yet can be inhibited by pharmacological and genetic interventions. As regulated necrosis (RN) plays a major role in both physiological scenarios (e.g., embryonic development) and pathological settings (e.g., ischemic disorders), consistent efforts have been made throughout the last decade toward the characterization of the molecular mechanisms that underlie this cell death modality. Contrarily to initial beliefs, RN does not invariably result from the activation of a receptor interacting protein kinase 3 (RIPK3)-dependent signaling pathway, but may be ignited by distinct molecular networks. Nowadays, various types of RN have been characterized, including (but not limited to) necroptosis, mitochondrial permeability transition (MPT)-dependent RN and parthanatos. Of note, the inhibition of only one of these modules generally exerts limited cytoprotective effects in vivo, underscoring the degree of interconnectivity that characterizes RN. Here, we review the signaling pathways, pathophysiological relevance and therapeutic implications of the major molecular cascades that underlie RN.
    Full-text · Article · Nov 2014 · Seminars in Cell and Developmental Biology
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    • "Infection can be tuned by signaling during entry and this can impact cell death by apoptosis, necrosis or pyroptosis, as well as innate signaling with pro-or anti-viral effects (Greber 2002; Faure and Rabourdin-Combe 2011; Mercer and Greber 2013). Cell death signals emerge from viral engagement of death receptors, signaling during uncoating and post-entry events (for some reviews, see Lamkanfi and Dixit 2010; Danthi 2011; Agol 2012; Kaiser et al., 2013). Innate immune responses comprise intrinsic mechanisms, which directly restrict viral replication and assembly, therefore leading to nonpermissiveness of the cell (Yan and Chen 2012). "
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