Murine Gamma Herpesvirus 68 Hijacks MAVS and IKKβ to Abrogate NFκB Activation and Antiviral Cytokine Production

Dong, Xiaonan; Feng, Pinghui

doi:10.1371/journal.ppat.1002336

Cited by 38 publications

(54 citation statements)

References 55 publications

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“…We found that IKKe, when activated by kGPCR, phosphorylated RelA at Ser468 and promoted its nuclear translocation, agreeing with the findings that RelA Ser468p up-regulates the expression of a subset of inflammatory genes (32). Interestingly, previous reports, including our findings from virus-infected cells (37), showed that the Ser468 phosphorylation primes RelA for degradation (38,39). By contrast, kGPCR expression activates IKKe that phosphorylates and activates RelA.…”

Section: Discussionsupporting

confidence: 91%

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi’s sarcoma. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKε is critically required for kGPCR tumorigenesis and links kGPCR to NF-κB activation. Using kGPCR-induced tumor models, we found that IKKε expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKε abolished tumor formation. Moreover, kGPCR interacted with and activated IKKε. Activated IKKε promoted NF-κB subunit RelA (also known as p65) phosphorylation, which correlated with NF-κB activation and inflammatory cytokine expression. The robust expression of IKKε and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKε effectively abrogated NF-κB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKε in promoting NF-κB activation and tumorigenesis induced by a viral GPCR.

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Section: Discussionsupporting

confidence: 91%

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Murine ␥-herpesvirus (gamma-HV68), a model system for KSHV and EBV, is known to activate IKK-␤. Interestingly, activated, phosphorylated IKK-␤ promotes viral replication, because the viral protein RTA (replication and transcription activator) is a phosphorylation target for IKK-␤ kinase activity (49). In contrast to this situation, in the case of vaccinia virus infection, the viral protein B14 modulates IKK-␤ kinase activity in a way that inhibits the phosphorylation of its downstream target IB␣ without exerting any influence on IKK-␣ activity (50,51).…”

Section: Mice a Infarmentioning

confidence: 99%

Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

Narayanan

Kehn-Hall

Senina

et al. 2012

Journal of Biological Chemistry

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Background: Rift Valley fever virus is a single-stranded RNA virus that causes disease in humans and livestock. Results: Rift Valley fever virus infection activates the host NFB signaling cascade. Conclusion: NFB inhibitors, particularly curcumin, down-regulate virus in both in vitro and in vivo models. Significance: Novel versions of host components resulting from an infection make them ideal therapeutic targets.

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“…6). The lytic transactivator RTA has been reported to inhibit multiple cell signaling pathways, including the TLR, MAVS, and NF-B signaling pathways (63)(64)(65). However, the reduction in IL-1␤ at 9 hpi did not require RTA or RTA-dependent viral genes.…”

Section: Discussionmentioning

confidence: 90%

“…Mutations in MHV68 orf50 severely limit viral gene expression and block virus replication (30,62). RTA has additional functions in host signaling pathways, including the degradation of NF-B signaling proteins, impairment of cytokine production, and interference with TLR signaling (63)(64)(65). To examine whether RTA or RTA-dependent gene expression drives suppression of IL-1␤, we infected BMDMs with a recombinant MHV68-ORF50stop virus (30) prior to LPS and ATP treatment and evaluated the intracellular and secreted levels of IL-1␤ at 9 hpi.…”

Section: Resultsmentioning

confidence: 99%

“…Although these data do not rule out a possible decrease in replication that is counterbalanced by a loss of immune control, the absence of any change in replication in primary fibroblasts or BMDMs suggests that caspase-1 does not influence virus replication at the cellular level. Acute MHV68 replication in the lungs of mice is enhanced in mice lacking either NF-B signaling components or IFN responses (63,69,70), including the cGAS cytoplasmic DNA sensor, which typically activates IRF3 signaling (71). The inflammasome is a powerful proinflammatory signaling pathway that restricts multiple pathogens (17,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

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Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

Cieniewicz

Dong

et al. 2015

J Virol

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Gammaherpesviruses establish lifelong infections that are associated with the development of cancer. These viruses subvert many aspects of the innate and adaptive immune response of the host. The inflammasome, a macromolecular protein complex that controls inflammatory responses to intracellular danger signals generated by pathogens, is both activated and subverted during human gammaherpesvirus infection in culture. The impact of the inflammasome response on gammaherpesvirus replication and latency in vivo is not known. Caspase-1 is the inflammasome effector protease that cleaves the proinflammatory cytokines interleukin-1␤ (IL-1␤) and IL-18. We infected caspase-1-deficient mice with murine gammaherpesvirus 68 (MHV68) and observed no impact on acute replication in the lung or latency and reactivation from latency in the spleen. This led us to examine the effect of viral infection on inflammasome responses in bone marrow-derived macrophages. We determined that infection of macrophages with MHV68 led to a robust interferon response but failed to activate caspase-1 or induce the secretion of IL-1␤. In addition, MHV68 infection led to a reduction in IL-1␤ production after extrinsic lipopolysaccharide stimulation or upon coinfection with Salmonella enterica serovar Typhimurium. Interestingly, this impairment occurred at the proIL-1␤ transcript level and was independent of the RTA, the viral lytic replication and transcription activator. Taken together, MHV68 impairs the inflammasome response by inhibiting IL-1␤ production during the initial stages of infection. IMPORTANCEGammaherpesviruses persist for the lifetime of the host. To accomplish this, they must evade recognition and clearance by the immune system. The inflammasome consists of proteins that detect foreign molecules in the cell and respond by secreting proinflammatory signaling proteins that recruit immune cells to clear the infection. Unexpectedly, we found that murine gammaherpesvirus pathogenesis was not enhanced in mice lacking caspase-1, a critical inflammasome component. This led us to investigate whether the virus actively impairs the inflammasome response. We found that the inflammasome was not activated upon macrophage cell infection with murine gammaherpesvirus 68. Infection also prevented the host cell inflammasome response to other pathogen-associated molecular patterns, indicated by reduced production of the proinflammatory cytokine IL-1␤ upon bacterial coinfection. Taken together, murine gammaherpesvirus impairment of the inflammatory cytokine IL-1␤ in macrophages identifies one mechanism by which the virus may inhibit caspase-1-dependent immune responses in the infected animal. G ammaherpesviruses establish lifelong latent infections that are associated with significant morbidity and the development of malignancies (1-3). Gammaherpesviruses initially infect the mucosal tissues of naive hosts and undergo productive replication prior to colonization of latency reservoirs, including B lymphocytes and macrophages (4-6). Murine gammaherpes...

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Murine Gamma Herpesvirus 68 Hijacks MAVS and IKKβ to Abrogate NFκB Activation and Antiviral Cytokine Production

Cited by 38 publications

References 55 publications

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

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