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Open AccessArticle

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

1
Institute of Genetics, Technische Universität Braunschweig, 38106 Braunschweig, Germany
2
Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
3
Institute of Virology, Technical University of Munich, School of Medicine, 81675 Munich, Germany
4
Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
5
Janssen Vaccines & Prevention BV, 2333 CN Leiden, The Netherlands
6
Department for Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
*
Author to whom correspondence should be addressed.
Microorganisms 2020, 8(6), 790; https://doi.org/10.3390/microorganisms8060790
Received: 7 May 2020 / Revised: 23 May 2020 / Accepted: 23 May 2020 / Published: 26 May 2020
(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)
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. View Full-Text
Keywords: herpesvirus; cytomegalovirus; pattern recognition receptor; cGAS; STING; RIG-I; TBK1; UL35; type I interferon; OGT herpesvirus; cytomegalovirus; pattern recognition receptor; cGAS; STING; RIG-I; TBK1; UL35; type I interferon; OGT
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Fabits, M.; Gonçalves Magalhães, V.; Chan, B.; Girault, V.; Elbasani, E.; Rossetti, E.; Saeland, E.; Messerle, M.; Pichlmair, A.; Lisnić, V.J.; Brinkmann, M.M. The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription. Microorganisms 2020, 8, 790.

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