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.

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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. "
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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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    • "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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