Journal
MICROORGANISMS
Volume 8, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/microorganisms8060790
Keywords
herpesvirus; cytomegalovirus; pattern recognition receptor; cGAS; STING; RIG-I; TBK1; UL35; type I interferon; OGT
Categories
Funding
- Technische Universitat Braunschweig
- Leibniz Universitat Hannover
- Ministry of Science and Culture (MWK) of Lower Saxony, Germany
- Helmholtz Association
- European Union's Horizon 2020 research and innovation program (H2020) under the Marie Sklodowska-Curie Innovative Training Networks Program [MSCA-ITN GA 675278 EDGE]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB900/3-158989968]
- Ph.D. scholarship of the international research training network group (IRTG) [1273]
- ERC [817798]
- European Regional Development Fund [KK.01.1.1.01.0006]
- European Research Council (ERC) [817798] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available