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

Research output: Contribution to journalArticlepeer-review

86 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 languageEnglish (US)
Pages (from-to)1385-1399
Number of pages15
JournalEMBO Journal
Volume35
Issue number13
DOIs
StatePublished - 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.

Keywords

  • herpes simplex virus
  • immune evasion
  • innate immunity
  • type I IFN

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