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The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-?B signaling and STING's dual role during MCMV infection.

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-?B signaling. Analysis of how m152 targets STING translocation reveals that STING activates NF-?B 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-?B response, providing an advantage in the establishment of an infection.

SUBMITTER: Stempel M

PROVIDER: S-EPMC6396373 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

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 M Chan Baca B Juranić Lisnić Vanda V Krmpotić Astrid A Hartung Josephine J Paludan Søren R SR Füllbrunn Nadia N Lemmermann Niels Aw NA Brinkmann Melanie M MM

The EMBO journal 20190129 5

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 <i>in vitro</i> an ...[more]

PMID: 30696688

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Project description:STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor ?B (NF-?B) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in response to STING activation by double-stranded DNA (dsDNA). Furthermore, TANK-binding kinase 1 (TBK1) associated with STING was found to facilitate dsDNA-mediated canonical activation of NF-?B as well as IRF3 to promote proinflammatory gene transcription. The triggering of NF-?B function was noted to require TRAF6 activation. Our findings detail a novel dsDNA-mediated NF-?B activation pathway facilitated through a STING-TRAF6-TBK1 axis and suggest a target for therapeutic intervention to plausibly stimulate antiviral activity or, alternatively, avert dsDNA-mediated inflammatory disease.The IKK complex, which is composed of two catalytic subunits, IKK? and IKK?, has been suggested to be essential for the activation of canonical NF-?B signaling in response to various stimuli, including cytokines (e.g., interleukin-1? [IL-1?] and tumor necrosis factor alpha [TNF-?]), Toll-like receptor (TLR) ligands (e.g., lipopolysaccharide [LPS]), and dsRNAs derived from viruses, or a synthetic analog. STING has been identified as a critical signaling molecule required for the detection of cytosolic dsDNAs derived from pathogens and viruses. However, little is known about how cytosolic dsDNA triggers NF-?B signaling. In the present study, we demonstrate that TBK1, identified as an IKK-related kinase, may predominantly control the activation of NF-?B in response to dsDNA signaling via STING through the IKK?? activation loop. Thus, our results establish TBK1 as a downstream kinase controlling dsDNA-mediated IRF3 and NF-?B signaling dependent on STING.

Dataset Information

The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-?B signaling and STING's dual role during MCMV infection.

Publications

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

Similar Datasets

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