Human Cytomegalovirus Tegument Protein pUL83 Inhibits IFI16-Mediated DNA Sensing for Immune Evasion
Open accessAbstract
Nuclear sensing of viral DNA has emerged as an essential step in innate immune responses against herpesviruses. Here, we provide mechanistic insight into host recognition of human cytomegalovirus (HCMV) and subsequent immune evasion by this prominent DNA virus. We establish that the interferon-inducible protein IFI16 acts as a nuclear DNA sensor following HCMV infection, binding viral DNA and triggering expression of antiviral cytokines via the STING-TBK1-IRF3 signaling pathway. The HCMV tegument protein pUL83 inhibits this response by interacting with the IFI16 pyrin domain, blocking its oligomerization upon DNA sensing and subsequent immune signals. pUL83 disrupts IFI16 by concerted action of its N- and C-terminal domains, in which an evolutionarily conserved N-terminal pyrin association domain (PAD) binds IFI16. Additionally, phosphorylation of the N-terminal domain modulates pUL83-mediated inhibition of pyrin aggregation. Collectively, our data elucidate the interplay between host DNA sensing and HCMV immune evasion, providing targets for restoring antiviral immunity.
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A pUL83-dependent inhibition of the IFI16 sensing function was identified.
“and of the pUL83-dependent inhibition of this sensing function (73)”
From The Impact of Mass Spectrometry–Based Proteomics on Fundamental Discoveries in Virology (2014) · cites this paper as [73]
One phosphorylation of HCMV pUL83, under host kinase control, blocks pUL83-dependent dispersal of cellular innate immunity effectors.
“Recently, we identified eight phosphosites within immunoaffinity-isolated pUL83 and established that one phosphorylation, under the control of host kinases, functions to block pUL83-dependent dispersal of cellular innate immunity effectors (73).”
From The Impact of Mass Spectrometry–Based Proteomics on Fundamental Discoveries in Virology (2014) · cites this paper as [73]
Eight phosphosites were identified within immunoaffinity-isolated HCMV pUL83.
“Recently, we identified eight phosphosites within immunoaffinity-isolated pUL83 and established that one phosphorylation, under the control of host kinases, functions to block pUL83-dependent dispersal of cellular innate immunity effectors (73).”
From The Impact of Mass Spectrometry–Based Proteomics on Fundamental Discoveries in Virology (2014) · cites this paper as [73]
IFI16 is a DNA sensor and effector of innate immune responses during viral infection, detecting viral DNA in both nucleus and cytoplasm.
“For instance, the DNA sensor IFI16 is an effector of innate immune responses during viral infection, detecting viral DNA in both the nucleus and the cytoplasm (71–73, 136, 137).”
From The Impact of Mass Spectrometry–Based Proteomics on Fundamental Discoveries in Virology (2014) · cites this paper as [73]
In HCMV infection, the major viral tegument protein binds IFI16 in the nucleus, blocking its oligomerization and antiviral cytokine response.
“the major viral tegument protein during HCMV infection was shown to bind to IFI16 in the nucleus, thereby blocking its ability to oligomerize and initiate antiviral cytokine response.”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [49]
Crosslinking was used to show that a host defense protein oligomerizes in response to viral infection.
“For example, crosslinking was used to show that a host defense protein oligomerizes in response to viral infection [49].”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [49]
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Greco, T. M., & Cristea, I. M. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.o116.066001 · Cited by 53 · see citing works
Self-citationMicroRNA Editing Facilitates Immune Elimination of HCMV Infected Cells
Nachmani, D., Zimmermann, A., Oiknine‐Djian, E., Weisblum, Y., Livneh, Y., Le‐Trilling, V. T. K., Galun, E., Hořejšı́, V., Isakov, O., Shomron, N., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1003963 · Cited by 53 · see citing works
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Interaction between HCMV pUL83 and human AIM2 disrupts the activation of the AIM2 inflammasome
Huang, Y., Ma, D., Huang, H., Lu, Y., Liao, Y., Liu, L., Liu, X., & Feng, F. (2017) · Virology Journal · doi:10.1186/s12985-016-0673-5 · Cited by 53 · see citing works
Justice, J. L., Kennedy, M. A., Hutton, J. E., Liu, D., Song, B., Phelan, B., & Cristea, I. M. (2021) · Science Advances · doi:10.1126/sciadv.abg6680 · Cited by 52 · see citing works
Self-citationcGAS-STING signaling pathway in intestinal homeostasis and diseases
Yang, Y., Wang, L., Peugnet-González, I., Parada‐Venegas, D., Dijkstra, G. D. H., & Faber, K. N. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1239142 · Cited by 51 · see citing works
The interferon-inducible DNA-sensor protein IFI16: a key player in the antiviral response.
Dell’Oste, V., Gatti, D., Ag, G., Gariglio, M., Landolfo, S., & Andrea, M. D. (2015) · PubMed · Cited by 51 · see citing works
IFI16 phase separation via multi-phosphorylation drives innate immune signaling
Liu, D., Lum, K. K., Treen, N., Núñez, C. T., Yang, J., Howard, T. R., Levine, M., & Cristea, I. M. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad449 · Cited by 50 · see citing works
Self-citationBiolatti, M., Dell’Oste, V., Pautasso, S., von Einem, J., Marschall, M., Plachter, B., Gariglio, M., Andrea, M. D., & Landolfo, S. (2016) · Journal of Virology · doi:10.1128/jvi.00923-16 · Cited by 50 · see citing works
Cytosolic DNA Sensing: The Field Narrows
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Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors
Unterholzner, L., & Almine, J. F. (2018) · Immunology · doi:10.1111/imm.13030 · Cited by 48 · see citing works
Liquid–liquid phase separation in innate immunity
Liu, D., Yang, J., & Cristea, I. M. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.04.009 · Cited by 51 · see citing works
Self-citationFan, Y.-H., Roy, S., Mukhopadhyay, R., Kapoor, A., Duggal, P., Wojcik, G. L., Pass, R. F., & Arav‐Boger, R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611711113 · Cited by 47 · see citing works
Targeting of the cGAS-STING system by DNA viruses
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Protect this house: cytosolic sensing of viruses
McFadden, M. J., Gokhale, N. S., & Horner, S. M. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.11.012 · Cited by 47 · see citing works
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Viral evasion of the interferon response at a glance
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Target Discovery for Host-Directed Antiviral Therapies: Application of Proteomics Approaches
Çakır, M., Obernier, K., Forget, A., & Krogan, N. J. (2021) · mSystems · doi:10.1128/msystems.00388-21 · Cited by 45 · see citing works
Diverse mechanisms evolved by DNA viruses to inhibit early host defenses
Crow, M. S., Lum, K. K., Sheng, X., Song, B., & Cristea, I. M. (2016) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2016.1226250 · Cited by 44 · see citing works
Self-citationRestructured membrane contacts rewire organelles for human cytomegalovirus infection
Cook, K. C., Tsopurashvili, E., Needham, J. M., Thompson, S. R., & Cristea, I. M. (2022) · Nature Communications · doi:10.1038/s41467-022-32488-6 · Cited by 43 · see citing works
Self-citationHarwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Übner, T., Munday, D. C., Nevels, M., & Paulus, C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005748 · Cited by 44 · see citing works
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Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure
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Interferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus Latency
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Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling
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Innate immune sensing of HIV-1 infection
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Human Cytomegalovirus Primary Infection and Reactivation: Insights From Virion-Carried Molecules
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Charge-Mediated Pyrin Oligomerization Nucleates Antiviral IFI16 Sensing of Herpesvirus DNA
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Self-citationA Mass Spectrometry View of Stable and Transient Protein Interactions
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Self-citationInnate Recognition of Alphaherpesvirus DNA
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Cytomegalovirus immune evasion of myeloid lineage cells
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Modulation of Innate Immune Signaling Pathways by Herpesviruses
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Modulation of the innate immune response by human cytomegalovirus
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Self-citationInfection-induced lysine lactylation enables herpesvirus immune evasion
Tyl, M. D., Merengwa, V. U., & Cristea, I. M. (2025) · Science Advances · doi:10.1126/sciadv.ads6215 · Cited by 33 · see citing works
Self-citation
- Authors
- Li, T., Chen, J., & Cristea, I. M.
- Affiliations
- Princeton University (US)
- Corresponding author
- Cristea, Ileana M.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 14
- Issue
- 5
- Pages
- 591-599
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC3876934
- OpenAlex
- W2033448230
- Cited by
- 226
- References
- 30
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 11 · 2023: 11 · 2022: 13 · 2021: 23 · 2020: 21 · 2019: 21 · 2018: 21 · 2017: 19 · 2016: 29 · 2015: 25 · 2014: 18 · 2013: 1
- FWCI
- 13.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DP1DA026192)
- National Institute of Allergy and Infectious Diseases (R21AI102187)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD073044)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- human cytomegalovirus, tegument proteins, IFI16, pyrin domain, immune evasion, herpesvirus, protein phosphorylation, antiviral cytokines, innate immunity
- MeSH terms
- Cell Line, Cytomegalovirus, DNA, Viral, Humans, Nuclear Proteins, Phosphoproteins, Protein Binding, Viral Matrix Proteins, Signal Transduction, Protein Interaction Domains and Motifs, Host-Pathogen Interactions, Immune Evasion
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