HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression

Maria H. Christensen; Søren B. Jensen; Juho J. Miettinen; Stefanie Luecke; Thaneas Prabakaran; Line S. Reinert; Thomas Mettenleiter; Zhijian J. Chen; David M. Knipe; Rozanne M. Sandri-Goldin; Lynn W. Enquist; Rune Hartmann; Trine H. Mogensen; Stephen A. Rice; Tuula A. Nyman; Sampsa Matikainen; Søren R. Paludan

doi:10.15252/embj.201593458

HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression

Maria H. Christensen, Søren B. Jensen, Juho J. Miettinen, Stefanie Luecke, Thaneas Prabakaran, Line S. Reinert, Thomas Mettenleiter, Zhijian J. Chen, David M. Knipe, Rozanne M. Sandri-Goldin, Lynn W. Enquist, Rune Hartmann, Trine H. Mogensen, Stephen A. Rice, Tuula A. Nyman, Sampsa Matikainen, Søren R. Paludan

Microbiology

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

127 Scopus citations

Abstract

Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS–STING–TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS–STING–TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.

Original language	English (US)
Pages (from-to)	1385-1399
Number of pages	15
Journal	EMBO Journal
Volume	35
Issue number	13
DOIs	https://doi.org/10.15252/embj.201593458
State	Published - Jul 1 2016

Bibliographical note

Funding Information:
We thank Kirsten S Petersen for technical assistance and Prof. Andrew Bowie for generous donation of reagents. This work was funded by The Danish Medical Research Council (grants no: 12-124330 and 11-107588), The Novo Nordisk Foundation, The Lundbeck Foundation (grant no R34-3855), Aarhus University Research Foundation (all to SRP), and by NIH grant AAI106934 to DMK. SL was supported by a scholarship from The Boehringer Ingelheim Fonds.

Publisher Copyright:
© 2016 The Authors

Keywords

herpes simplex virus
immune evasion
innate immunity
type I IFN

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10.15252/embj.201593458

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Christensen, M. H., Jensen, S. B., Miettinen, J. J., Luecke, S., Prabakaran, T., Reinert, L. S., Mettenleiter, T., Chen, Z. J., Knipe, D. M., Sandri-Goldin, R. M., Enquist, L. W., Hartmann, R., Mogensen, T. H., Rice, S. A., Nyman, T. A., Matikainen, S., & Paludan, S. R. (2016). HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. EMBO Journal, 35(13), 1385-1399. https://doi.org/10.15252/embj.201593458

Christensen, MH, Jensen, SB, Miettinen, JJ, Luecke, S, Prabakaran, T, Reinert, LS, Mettenleiter, T, Chen, ZJ, Knipe, DM, Sandri-Goldin, RM, Enquist, LW, Hartmann, R, Mogensen, TH, Rice, SA, Nyman, TA, Matikainen, S & Paludan, SR 2016, 'HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression', EMBO Journal, vol. 35, no. 13, pp. 1385-1399. https://doi.org/10.15252/embj.201593458

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abstract = "Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS–STING–TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS–STING–TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.",

keywords = "herpes simplex virus, immune evasion, innate immunity, type I IFN",

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note = "Funding Information: We thank Kirsten S Petersen for technical assistance and Prof. Andrew Bowie for generous donation of reagents. This work was funded by The Danish Medical Research Council (grants no: 12-124330 and 11-107588), The Novo Nordisk Foundation, The Lundbeck Foundation (grant no R34-3855), Aarhus University Research Foundation (all to SRP), and by NIH grant AAI106934 to DMK. SL was supported by a scholarship from The Boehringer Ingelheim Fonds. Publisher Copyright: {\textcopyright} 2016 The Authors",

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AU - Miettinen, Juho J.

AU - Luecke, Stefanie

AU - Prabakaran, Thaneas

AU - Reinert, Line S.

AU - Mettenleiter, Thomas

AU - Chen, Zhijian J.

AU - Knipe, David M.

AU - Sandri-Goldin, Rozanne M.

AU - Enquist, Lynn W.

AU - Hartmann, Rune

AU - Mogensen, Trine H.

AU - Rice, Stephen A.

AU - Nyman, Tuula A.

AU - Matikainen, Sampsa

AU - Paludan, Søren R.

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N2 - Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS–STING–TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS–STING–TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.

AB - Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS–STING–TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS–STING–TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.

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