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Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1.

ABSTRACT: Expression of the antiviral cytokines IFN-alpha/beta is among the most potent innate defenses of higher vertebrates to virus infections, which is controlled by the inducible transcription factor IFN regulatory factor (IRF)3. Borna disease virus (BDV) establishes persistent noncytolytic infections in animals and tissue culture cells, indicating that it can circumvent this antiviral reaction by an unexplained activity. In this study, we identify the BDV P protein as microbial gene product that associates with and inhibits the principal regulatory kinase of IRF3, Traf family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK-1). We demonstrate that the P protein counteracts TBK-1-dependent IFN-beta expression in cells and, hence, the establishment of an antiviral state. Furthermore, our data show that the BDV P protein itself is phosphorylated by TBK-1, suggesting that P functions as a viral decoy substrate that prevents activation of cellular target proteins of TBK-1. Thus, our findings provide evidence for a previously undescribed mechanism by which a viral protein interferes with the induction of the antiviral IFN cascade.

SUBMITTER: Unterstab G

PROVIDER: S-EPMC1224622 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1.

Unterstab Gunhild G Ludwig Stephan S Anton Aline A Planz Oliver O Dauber Bianca B Krappmann Daniel D Heins Gudrun G Ehrhardt Christina C Wolff Thorsten T

Proceedings of the National Academy of Sciences of the United States of America 20050909 38

Expression of the antiviral cytokines IFN-alpha/beta is among the most potent innate defenses of higher vertebrates to virus infections, which is controlled by the inducible transcription factor IFN regulatory factor (IRF)3. Borna disease virus (BDV) establishes persistent noncytolytic infections in animals and tissue culture cells, indicating that it can circumvent this antiviral reaction by an unexplained activity. In this study, we identify the BDV P protein as microbial gene product that ass ...[more]

PMID: 16155125

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Project description:High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-?), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-? has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-? by hr-HPV raises the possibility that IFN-? has anti-HPV activity. Using doxycycline-inducible IFN-? expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-? inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited at 4 to 6 h after IFN-? expression. This was also observed with recombinant IFN-?, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-?-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-? acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNA interference (RNAi) and cotransfection experiments indicated that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-?. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-? to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity.High-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN-?, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-? rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV.

Project description:Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs 1 to 4), all of which are expressed during lytic replication and inhibit a variety of antiviral signaling pathways. Viral IRFs 1, 2, and 3 are also expressed during latency in primary effusion lymphoma (PEL) cells, and vIRF-1 and vIRF-3 have been reported to promote PEL cell viability. Viral IRFs 1, 3, and 4 are known to interact with ubiquitin-specific protease 7 (USP7); interactions of vIRF-1 and vIRF-3 with USP7 promote PEL cell viability and regulate productive replication. Here, we report that vIRF-2 also targets USP7, utilizing a PSTS motif matching the USP7 N-terminal domain-binding A/PxxS consensus, but uniquely requires catalytic domain residues for intracellular interaction. In functional and mechanistic analyses, tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling and associated polyubiquitination of TRAFs 3 and 6, specifically, were regulated negatively by USP7 and positively by vIRF-2-USP7 interaction, the latter competing for USP7-TRAF association. Using depletion, depletion-complementation, and targeted mutagenesis approaches, vIRF-2 was determined to promote latent PEL cell viability, likely independently of USP7 interaction, while lytic replication was inhibited by vIRF-2, in part or in whole via USP7 interaction. Together, our data identify a new molecular determinant of USP7 recognition, TRAF3/6-specific targeting by the deubiquitinase, associated activation of these TRAFs by vIRF-2, and activities of vIRF-2 and vIRF-2-USP7 interaction in HHV-8 latent and lytic biology.IMPORTANCE Human herpesvirus 8-encoded IRF homologues were the first to be identified in a virus. Through inhibitory interactions with cellular IRFs and other mediators of antiviral signaling, the vIRFs are believed to be essential for productive replication and also for latency in particular cell types. The deubiquitinase USP7 is a regulator of key cellular pathways, modulates HHV-8 latent and lytic infection, and is targeted by vIRFs 1, 3, and 4. Here, we report that vIRF-2 also interacts with USP7, via a means distinguishable from USP7 interactions with other vIRFs and other proteins, that this interaction modulates antiviral signaling via disruption of USP7 interactions with innate immune signaling proteins TRAF3 and TRAF6, and that vIRF-2 targeting of USP7 regulates HHV-8 productive replication. The presented data are the first to identify vIRF-2 targeting of USP7 and its role in HHV-8 biology, expanding our understanding of the repertoire and importance of virus-host interactions.

Dataset Information

Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1.

Publications

Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1.

Similar Datasets

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