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The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-κB signaling and STING's dual role during MCMV infection.
Stempel, Markus Chan, Baca Juranić Lisnić, Vanda Krmpotić, Astrid Hartung, Josephine Paludan, Søren R Füllbrunn, Nadia Lemmermann, Niels Aw Brinkmann, Melanie M
Stempel, Markus
Chan, Baca
Juranić Lisnić, Vanda
Krmpotić, Astrid
Hartung, Josephine
Paludan, Søren R
Füllbrunn, Nadia
Lemmermann, Niels Aw
Brinkmann, Melanie M
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2019-01-29
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Abstract
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.
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en
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1460-2075
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Attribution-NonCommercial-ShareAlike 4.0 International