Viral appropriation of apoptotic and NF‐κB signaling pathways

Bowie, Andrew; Zhan, Jun; Marshall, William L.

doi:10.1002/jcb.20026

Cited by 38 publications

(34 citation statements)

References 66 publications

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“…In some cases, apoptosis triggered by viral infection may serve as a component of host defense to limit viral replication or spread. In other instances, apoptosis may enhance viral infection by facilitating viral dissemination or allowing virus to evade host inflammatory responses (5,6,63). Apoptosis plays an important role in the various patterns of disease caused by reovirus infection (22,23,53,54).…”

Section: Discussionmentioning

confidence: 99%

IκB Kinase Subunits α and γ Are Required for Activation of NF-κB and Induction of Apoptosis by Mammalian Reovirus

Hansberger

Campbell

Danthi

et al. 2007

J Virol

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Reoviruses induce apoptosis both in cultured cells and in vivo. Apoptosis plays a major role in the pathogenesis of reovirus encephalitis and myocarditis in infected mice. Reovirus-induced apoptosis is dependent on the activation of transcription factor NF-B and downstream cellular genes. To better understand the mechanism of NF-B activation by reovirus, NF-B signaling intermediates under reovirus control were investigated at the level of Rel, IB, and IB kinase (IKK) proteins. We found that reovirus infection leads initially to nuclear translocation of p50 and RelA, followed by delayed mobilization of c-Rel and p52. This Mammalian reoviruses are nonenveloped viruses that contain a genome of 10 segments of double-stranded RNA (52). Following infection of newborn mice, reovirus disseminates systemically, causing injury to the central nervous system (CNS), heart, and liver (76). Apoptosis induced by reovirus appears to be the primary mechanism for virus-induced encephalitis (53, 54, 59) and myocarditis (22,23,54). Disassembly of internalized virus in the endocytic pathway provides the initial viral trigger for stimulating the signaling pathways that elicit an apoptotic response (19,21).Transcription factor NF-B plays an important regulatory role in apoptosis evoked by reovirus in cultured cells (20) and in vivo (54). Inducible members of the NF-B family are sequestered in the cytoplasm by inhibitory IB proteins, including IB␣, IB␤, IBε, and p100/NF-B2 (3,31,68,79,82). In response to a wide variety of NF-B inducers, IB proteins are phosphorylated at specific serine residues, earmarking these molecules for destruction by the ubiquitin-proteasome pathway (7,12,31,56,75,82). Phosphorylation of IB proteins is mediated by cytokine-inducible IB kinases (IKKs) IKK␣ and IKK␤ (47,78), which can form higher-order complexes containing a regulatory subunit called IKK␥/Nemo (26,50,62,88,91). A primary function of IKK␤ is to modulate the inhibitory interaction of IB␣ with the prototypical form of NF-B containing p50/RelA dimers (25,26,50,58,69). This regulatory circuit, termed the classical pathway of NF-B activation, is strictly dependent on the presence of IKK␥/Nemo (64,65,88). In contrast, IKK␣ functions in an alternative IKK␥-independent pathway of NF-B activation that leads to the proteolytic processing of p100 and the production of a functional p52 Rel subunit (16,66,71). Unlike the classical IKK␤-directed pathway of NF-B activation, the alternative pathway involving IKK␣ is dependent on its prior phosphorylation by NF-Binducing kinase (NIK) (43,66,85). In addition to the cytoplasmic function of IKK␣, a nuclear role for IKK␣ in the transcriptional activation of NF-B-responsive genes has been suggested by in vitro studies (1,32,33,41,48,69,87).To better understand the mechanism of NF-B activation by reovirus, we conducted experiments to define the NF-B/Rel, IB, and IKK proteins that are under reovirus control. These studies revealed that NF-B/Rel proteins are mobilized to the nuclear compartment with biphasic kinetics follo...

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Section: Discussionmentioning

confidence: 99%

IκB Kinase Subunits α and γ Are Required for Activation of NF-κB and Induction of Apoptosis by Mammalian Reovirus

Hansberger

Campbell

Danthi

et al. 2007

J Virol

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“…35 Finally, the viral proteins A46R and A52R from poxviruses can also target TLR-signaling pathways to downregulate inflammatory responses. A52R physically interacts with TRAF6 and IRAK2 whereas the direct target of A46R is still unknown (reviewed by Bowie et al 36 ). An interesting area of research in the future will be to examine if other microbial pathogens can interfere with TLR signaling in order to escape immune detection.…”

Section: Putting the Brake On Tlr Responsesmentioning

confidence: 99%

TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.

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“…As an example of a hijacking strategy in HIVAN, HIV-1 is widely known to interfere with the signal transduction pathway that activates the transcription factor NF-B (27,28). NF-B is the central regulator of most immune and inflammatory processes and controls the transcription of many host genes (29).…”

Section: Hijacking Strategiesmentioning

confidence: 99%

Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis

Bruggeman

2007

Clinical Journal of the American Society of Nephrology

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Viruses cannot autonomously replicate but must rely on the host cellular machinery to support their life cycle. Through natural selection, viruses have evolved strategies to co-opt the host organism to be a better site for their propagation. Some of these strategies are directed at the cellular machinery and involve complicated and ingenious solutions to optimize infection, replication, viral gene expression, and new virion assembly and shedding. Other strategies are directed at the host's innate and adaptive immune systems that permit the virus to evade clearance mechanisms. The more common pathogenic viral infections in nephrology-cytomegalovirus, HIV-1, hepatitis C virus, polyomavirus BK, and parvovirus B19 -all have acquired subversion strategies that benefit the virus but because they interfere with normal cellular and immune processes also have become pathogenic to the host. In addition, the highly prevalent viruses cytomegalovirus, BK, and B19 cause severe disease only in the setting of immunosuppression, revealing the very delicate balance that some viruses have achieved with their host's immune system. Thus, selective pressure for survival drives both the evolution of more sophisticated viruses and the host immune system as it evolves to combat the environment of adapting and emerging infectious agents. Understanding the molecular mechanisms of these viral subversion strategies may reveal new targets for the development of highly specific antiviral therapies and also aid vaccine development.

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Viral appropriation of apoptotic and NF‐κB signaling pathways

Cited by 38 publications

References 66 publications

IκB Kinase Subunits α and γ Are Required for Activation of NF-κB and Induction of Apoptosis by Mammalian Reovirus

IκB Kinase Subunits α and γ Are Required for Activation of NF-κB and Induction of Apoptosis by Mammalian Reovirus

TIR, CARD and PYRIN: three domains for an antimicrobial triad

Viral Subversion Mechanisms in Chronic Kidney Disease Pathogenesis

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