The herpesviral antagonist m152 reveals differential activation of STING‐dependent IRF and NF‐κB signaling and STING's dual role during MCMV infection

• Markus Stempel ^[1] ; Baca Chan ^[1] ; Vanda Juranić Lisnić ^[2] ; Astrid Krmpotić ^[2] ; Josephine Hartung ^[1] ; Søren R Paludan ^[3] ; Nadia Füllbrunn ^[1] ; Niels AW Lemmermann ^[4] ; Melanie M Brinkmann ^[1]
  1. [1] Helmholtz Centre for Infection Research

     Helmholtz Centre for Infection Research

     Kreisfreie Stadt Braunschweig, Alemania

     
  2. [2] University of Rijeka

     University of Rijeka

     Croacia

     
  3. [3] 3 Department of Biomedicine Aarhus Research Center for Innate Immunology University of Aarhus Aarhus Denmark
  4. [4] 4 Institute for Virology and Research Center for Immunotherapy University Medical Center of the Johannes Gutenberg‐University Mainz Mainz Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 5, 2019
• Idioma: inglés
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• Resumen

  • Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING‐mediated IRF signaling, it did not affect STING‐mediated NF‐κB signaling. Analysis of how m152 targets STING translocation reveals that STING activates NF‐κB signaling already from the ER prior to its trafficking to the Golgi. Strikingly, this response is important to promote early MCMV replication. Our results show that MCMV has evolved a mechanism to specifically antagonize the STING‐mediated antiviral IFN response, while preserving its pro‐viral NF‐κB response, providing an advantage in the establishment of an infection.