SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses

Dominik Dornfeld; Alexandra H. Dudek; Thibaut Vausselin; Sira C. Günther; Judd F. Hultquist; Sebastian Giese; Daria Khokhlova-Cubberley; Yap C. Chew; Nevan J. Krogan; Adolfo Garcia-Sastre; Martin Schwemmle; Megan L. Shaw

doi:10.1038/s41598-018-20458-2

SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses

Dominik Dornfeld, Alexandra H. Dudek, Thibaut Vausselin, Sira C. Günther, Judd F. Hultquist, Sebastian Giese, Daria Khokhlova-Cubberley, Yap C. Chew, Nevan J. Krogan, Adolfo Garcia-Sastre^*, Martin Schwemmle, Megan L. Shaw

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV.

Original language	English (US)
Article number	2092
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-20458-2
State	Published - Dec 1 2018

Funding

We thank Philipp P. Petric for technical assistance, Richard E. Randall for providing A549 cells stably expressing MxA or shMxA and Georg Kochs for providing the MxA-specific antibody. We thank Dan Felsenfeld, Pamela Cheung and Sharmila Sivendran from the Integrated Screening Core at Mount Sinai for technical assistance with the siRNA screen. This study was supported in part by funds from the German Research Foundation (DFG; SFB 1160, project 13) to M.S., the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School) to A.H.D, and National Institutes of Health (NIH) (grants R21AI102169 to M.L.S. and U19AI106754 to A.G.S., N.J.K. and M.L.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Dornfeld, D., Dudek, A. H., Vausselin, T., Günther, S. C., Hultquist, J. F., Giese, S., Khokhlova-Cubberley, D., Chew, Y. C., Krogan, N. J., Garcia-Sastre, A., Schwemmle, M., & Shaw, M. L. (2018). SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses. Scientific reports, 8(1), Article 2092. https://doi.org/10.1038/s41598-018-20458-2

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abstract = "The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV.",

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AU - Dudek, Alexandra H.

AU - Vausselin, Thibaut

AU - Günther, Sira C.

AU - Hultquist, Judd F.

AU - Giese, Sebastian

AU - Khokhlova-Cubberley, Daria

AU - Chew, Yap C.

AU - Krogan, Nevan J.

AU - Garcia-Sastre, Adolfo

AU - Schwemmle, Martin

AU - Shaw, Megan L.

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N2 - The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV.

AB - The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV.

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SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses

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