Abstract
Infection of mammalian cells with viruses activates NF-κB to induce the expression of cytokines and chemokines and initiate an antiviral response. Here, we show that a vaccinia virus protein mimics the transactivation domain of the p65 subunit of NF-κB to inhibit selectively the expression of NF-κB-regulated genes. Using co-immunoprecipitation assays, we found that the vaccinia virus protein F14 associates with NF-κB co-activator CREB-binding protein (CBP) and disrupts the interaction between p65 and CBP. This abrogates CBP-mediated acetylation of p65, after which it reduces promoter recruitment of the transcriptional regulator BRD4 and diminishes stimulation of NF-κB-regulated genes CXCL10 and CCL2. Recruitment of BRD4 to the promoters of NFKBIA and CXCL8 remains unaffected by either F14 or JQ1 (a competitive inhibitor of BRD4 bromodomains), indicating that BRD4 recruitment is acetylation-independent. Unlike other viral proteins that are general antagonists of NF-κB, F14 is a selective inhibitor of NF-κB-dependent gene expression. An in vivo model of infection demonstrated that F14 promotes virulence. Molecular mimicry of NF-κB may be conserved because other orthopoxviruses, including variola, monkeypox and cowpox viruses, encode orthologues of F14.
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Data availability
The authors declare that the main data supporting the findings of this study are available within the article and its Supplementary Information. Poxvirus nucleotide sequences mentioned in this study are publicly available on NCBI GenBank: VACV Western Reserve (NC_006998.1), VACV Copenhagen (M35027.1), VACV Modified Virus Ankara (AY603355.1), horsepox virus isolate MNR-76 (DQ792504.1), monkeypox virus Zaire-96-I-16 (NC_003310.10, cowpox virus Brighton Red (NC_003663.2), variola virus India-1967 (NC_001611.1), camelpox virus CMS (AY009089.1), taterapox virus Dahomey 1968 (DQ437594.1), ectromelia virus Moscow (AF012825.2), raccoonpox virus Herman (NC_027213.1), premodern variola virus (LR800247.1, LR800244.1, LR800245.1, LR800246.1) and variola virus VD21 (KY358055.1). Source data are provided with this paper.
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Acknowledgements
We thank R. Seear, S. Macilwee and J. Milburn for technical support and F. Pfaff and M. Beer (Friedrich-Loeffler-Institut, Germany) for help with access to the cowpox RNA sequencing dataset. We also thank J. Doorbar and C. Crump (Department of Pathology, University of Cambridge, UK), T. Kouzarides (Department of Pathology and The Gurdon Institute, University of Cambridge, UK) and G. Blobel (University of Pennsylvania, Philadelphia, USA) for providing us with reagents. We are grateful to T. Kouzarides for helpful advice and to C. Talbot-Cooper for critical reading of the manuscript. This work was supported by grant no. 090315 from the Wellcome Trust (to G.L.S.). B.Y-W.C.’s laboratory is funded by the Medical Research Council (grant no. MR/R021821/1), the Biotechnology and Biological Sciences Research Council (grant no. BB/V017780.1) and Isaac Newton Trust (grant no. G101522). J.D.A. was a postdoctoral fellow of the Science without Borders programme from CNPq-Brazil (grant no. 235246/2014-0). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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J.D.A., A.A.T. and G.L.S. conceived the idea. J.D.A., H.R., A.A.T., E.V.S., C.A.M., A.J.B., M.P.B. and B.Y-W.C. developed the methodology. J.D.A., H.R., A.A.T. and E.V.S. validated the results. J.D.A. and H.R. undertook the formal analysis. J.D.A., H.R., A.A.T. and E.V.S. undertook investigation. A.A.T., C.A.M., A.J.B., B.Y-W.C. and G.L.S. obtained resources. J.D.A. undertook data curation. J.D.A. wrote the original draft. J.D.A., H.R., A.A.T., C.A.M., A.J.B., B.Y-W.C. and G.L.S. reviewed and edited the manuscript. J.D.A. prepared visualization. J.D.A. and G.L.S. supervised the work. J.D.A. and G.L.S. were project administrators. J.D.A. and G.L.S. obtained funding. A.A.T., C.A.M., A.J.B., B.Y-W.C. and G.L.S. contributed resources.
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Extended data
Extended Data Fig. 1 Screen of VACV strain WR ORFs for NF-κB inhibitory activity.
NF-κB-dependent luciferase activity in HEK 293T cells transfected with vectors expressing the indicated VACV proteins or empty vector (EV), and stimulated with TNF-α. Negative (EV, GFP, and N2) and positive (B14) controls are highlighted in the dashed black square, whilst F14 is highlighted in the dashed red square. Means + s.d. (n = 3-4 per condition) are shown.
Extended Data Fig. 2 Virulence of VACV mutant lacking F14 in the intranasal mouse model of infection.
BALB/c mice were infected intranasally with 5×103 p.f.u. of the indicated VACV strains and their body mass was measured daily. Body mass is expressed as the percentage ± s.e.m. of the mean of the same group of mice on day 0 (n = 5 mice).
Extended Data Fig. 3 Replication and spread of VACV mutant lacking F14 in cell culture.
(a,b) HeLa cells were infected with the indicated VACV strains (5 p.f.u./cell) and virus titres associated with the cells (a) and in the supernatants (b) were determined by plaque assay. Means (n = 2 per condition) are shown. (c) Plaque formation by the indicated VACV strains on BS-C-1 cells.
Extended Data Fig. 4 F14 does not inhibit the nuclear translocation of NF-κB subunit p65.
a, T-REx-293 cells inducibly expressing the empty vector (EV) or VACV proteins B14, C6, or F14, were induced with doxycycline and stimulated with TNF-α. Fixed and permeabilised cells were stained with anti-p65 antibody and DAPI, and analysed by confocal microscopy. Scale bars (50 μm) are shown in the bottom right of each micrograph. Representative micrographs of quantitative analysis shown in Fig. 1l. b, Flow cytometry analysis of T-REx-293-F14 induced with doxycycline in the absence and in the presence of the proteasome inhibitor MG132. F14 presence was detected by staining with an anti-FLAG antibody.
Extended Data Fig. 5 F14 inhibits NF-κB at or downstream of p65.
NF-κB activity in HEK 293 T cells transfected with vectors expressing p65, VACV proteins B14 or F14, or empty vector (EV). Top panel: Means + s.d. (n = 4 per condition) are shown. Statistical significance was determined by unpaired two-tailed Student’s t-test. Bottom panel: Immunoblotting. Protein molecular mass markers in kDa are shown on the left of the blots. Immunoblots of tagged proteins are labelled with the protein name followed by the epitope tag antibody in parentheses. When multiple tagged proteins are shown in the same immunoblot, each protein is indicated by a red arrowhead.
Extended Data Fig. 6 F14 is unique among known viral inhibitors of NF-κB.
(a) Top: Amino acid sequence of the TAD of HSV-1 VP16 with the acidic activation domain similar to p65 highlighted in red, and hydrophobic residues (Φ) are indicated. Middle: NF-κB-dependent luciferase activity in HEK 293T cells transfected with vectors expressing VP16, VP16 mutant, or empty vector (EV), and stimulated with TNF-α. Bottom: Immunoblotting. (b) Top: Amino acid residues 61-98 from HPV16 protein E7 encompassing a ΦXXΦΦ motif containing and preceded by negatively charged residues. Highlighted are two residues mutated to disrupt this motif. Middle: NF-κB-dependent luciferase activity in HEK 293T cells expressing E7 and two mutants as described in (a). Bottom: Immunoblotting. Means + s.d. (n = 4 per condition) are shown. c, Lysates from transfected HEK 293T cells were immunoprecipitated with anti-HA. Immunoblots are representative of two independent experiments. Protein molecular masses in kDa are shown on the left of the blots. Immunoblots of tagged proteins are labelled with the protein name followed the epitope tag antibody in parentheses. When multiple tagged proteins are shown in the same immunoblot, each protein is indicated a red arrowhead. Statistical significance was determined by the Student’s t-test.
Extended Data Fig. 7 F14 suppresses expression of a subset of NF-κB-responsive genes.
(a-d) RT-qPCR analysis of NF-κB-responsive gene expression in inducible T-REx-293 cells induced with doxycycline overnight to express VACV proteins F14 or C6, and stimulated with TNF-α. Means (n = 2 per condition) are shown. e, Immunoblotting of lysates of inducible T-REx-293 cell lines induced with doxycycline overnight. Data are representative of two independent experiments. Protein molecular masses in kDa are shown on the left of the blots.
Extended Data Fig. 8 F14 suppresses expression of CXCL10, but not CXCL8, after stimulation with TNF-α.
This shows data normalized for presentation in Fig. 5c,f. ELISA of CXCL8 (a) and CXCL10 (b) in culture supernatants from T-REx-293 cells inducibly expressing the empty vector (EV) or VACV proteins B14, C6, or F14, induced with doxycycline and stimulated with TNF-α. Means + s.d. (n = 3 per condition) are shown. Statistical significance was determined by the Student’s t-test.
Extended Data Fig. 9 JQ1 reduces BRD4 occupancy on CCND1 gene promoter.
Chromatin immunoprecipitation (ChIP) with anti-BRD4 antibody or control IgG, and qPCR for the promoters of CCND1 gene. T-REx-293 cells were treated with JQ1 and stimulated with TNF-α. Means + s.d. (n = 6 per condition from two independent experiments). Statistical significance was determined by the Student’s t-test.
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Albarnaz, J.D., Ren, H., Torres, A.A. et al. Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat Microbiol 7, 154–168 (2022). https://doi.org/10.1038/s41564-021-01004-9
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DOI: https://doi.org/10.1038/s41564-021-01004-9
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