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Murine cytomegalovirus virion-associated protein M45 mediates rapid NF-?B activation after infection.

ABSTRACT: Murine cytomegalovirus (MCMV) rapidly induces activation of nuclear factor ?B (NF-?B) upon infection of host cells. After a transient phase of activation, the MCMV M45 protein blocks all canonical NF-?B-activating pathways by inducing the degradation of the gamma subunit of the inhibitor of ?B kinase complex (IKK?; commonly referred to as the NF-?B essential modulator [NEMO]). Here we show that the viral M45 protein also mediates rapid NF-?B activation immediately after infection. MCMV mutants lacking M45 or expressing C-terminally truncated M45 proteins induced neither NF-?B activation nor transcription of NF-?B-dependent genes within the first 3 h of infection. Rapid NF-?B activation was absent in MCMV-infected NEMO-deficient fibroblasts, indicating that activation occurs at or upstream of the IKK complex. NF-?B activation was strongly reduced in murine fibroblasts lacking receptor-interacting protein 1 (RIP1), a known M45-interacting protein, but was restored upon complementation with murine RIP1. However, the ability of M45 to interact with RIP1 and NEMO was not sufficient to induce NF-?B activation upon infection. In addition, incorporation of the M45 protein into virions was required. This was dependent on a C-terminal region of M45, which is not required for interaction with RIP1 and NEMO. We propose a model in which M45 delivered by viral particles activates NF-?B, presumably involving an interaction with RIP1 and NEMO. Later in infection, expression of M45 induces the degradation of NEMO and the shutdown of canonical NF-?B activation.Transcription factor NF-?B is an important regulator of innate and adaptive immunity. Its activation can be beneficial or detrimental for viral pathogens. Therefore, many viruses interfere with NF-?B signaling by stimulating or inhibiting the activation of this transcription factor. Cytomegaloviruses, opportunistic pathogens that cause lifelong infections in their hosts, activate NF-?B rapidly and transiently upon infection but block NF-?B signaling soon thereafter. Here we report the surprising finding that the murine cytomegalovirus protein M45, a component of viral particles, plays a dual role in NF-?B signaling. It not only blocks NF-?B signaling later in infection but also triggers the rapid activation of NF-?B immediately following virus entry into host cells. Both activation and inhibition involve M45 interaction with the cellular signaling mediators RIP1 and NEMO. Similar dual functions in NF-?B signaling are likely to be found in other viral proteins.

SUBMITTER: Krause E

PROVIDER: S-EPMC4136316 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Murine cytomegalovirus virion-associated protein M45 mediates rapid NF-κB activation after infection.

Krause Eva E de Graaf Miranda M Fliss Patricia M PM Dölken Lars L Brune Wolfram W

Journal of virology 20140618 17

<h4>Unlabelled</h4>Murine cytomegalovirus (MCMV) rapidly induces activation of nuclear factor κB (NF-κB) upon infection of host cells. After a transient phase of activation, the MCMV M45 protein blocks all canonical NF-κB-activating pathways by inducing the degradation of the gamma subunit of the inhibitor of κB kinase complex (IKKγ; commonly referred to as the NF-κB essential modulator [NEMO]). Here we show that the viral M45 protein also mediates rapid NF-κB activation immediately after infect ...[more]

PMID: 24942588

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Project description:The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors, including virus infections, and triggers a powerful (proinflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as "inside-out" NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a noncanonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights into the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar "inside-out" nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (proinflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host driven and that its potential antiviral consequences are actively inhibited by the virus.

Dataset Information

Murine cytomegalovirus virion-associated protein M45 mediates rapid NF-?B activation after infection.

Publications

Murine cytomegalovirus virion-associated protein M45 mediates rapid NF-κB activation after infection.

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