Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein
Open accessAbstract
Innate sensing of microbial components is well documented to occur at many cellular sites, including at the cell surface, in the cytosol, and in intracellular vesicles, but there is limited evidence of nuclear innate signaling. In this study we have defined the mechanisms of interferon regulatory factor-3 (IRF-3) signaling in primary human foreskin fibroblasts (HFF) infected with herpes simplex virus 1 (HSV-1) in the absence of viral gene expression. We found that the interferon inducible protein 16 (IFI16) DNA sensor, which is required for induction of IRF-3 signaling in these cells, is nuclear, and its localization does not change detectably upon HSV-1 d 109 infection and induction of IRF-3 signaling. Consistent with the IFI16 sensor being nuclear, conditions that block viral DNA release from incoming capsids inhibit IRF-3 signaling. An unknown factor must be exported from the nucleus to activate IRF-3 through cytoplasmic STING, which is required for IRF-3 activation and signaling. However, when the viral ICP0 protein is expressed in the nucleus, it causes the nuclear relocalization and degradation of IFI16, inhibiting IRF-3 signaling. Therefore, HSV-1 infection is sensed in HFF by nuclear IFI16 upon release of encapsidated viral DNA into the nucleus, and the viral nuclear ICP0 protein can inhibit the process by targeting IFI16 for degradation. Together these results define a pathway for nuclear innate sensing of HSV DNA by IFI16 in infected HFF and document a mechanism by which a virus can block this nuclear innate response.
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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 [72]
In HSV-1-infected cells, ICP0 is the most abundant viral interaction with IFI16 at 3 and 8 hpi, and ICP0 targets IFI16 for proteasome-dependent degradation, inhibiting IFI16-mediated immune responses.
“the HSV-1 immediate-early transactivating protein ICP0 was determined to be the most abundant viral interaction with IFI16. Further functional analyses [18] provided additional support for the current model that during early stages of HSV-1 infection, ICP0 employs a virus immune evasion strategy mediated by protein associations to target IFI16 for proteasome-dependent degradation. This early assoc”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [19]
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- Authors
- Orzalli, M. H., DeLuca, N. A., & Knipe, D. M.
- Affiliations
- Harvard University (US)
- University of Pittsburgh (US)
- Corresponding author
- Knipe, David M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-10
- Volume
- 109
- Issue
- 44
- Pages
- E3008-17
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3497734
- OpenAlex
- W2163362670
- Cited by
- 422
- References
- 65
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 21 · 2023: 15 · 2022: 25 · 2021: 35 · 2020: 32 · 2019: 44 · 2018: 30 · 2017: 24 · 2016: 38 · 2015: 49 · 2014: 34 · 2013: 39 · 2012: 3
- FWCI
- 17.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI099081, AI099081, R01AI044821, P01AI083215, AI83215)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- IFI16, herpes simplex virus type 1, ICP0, viral DNA sensing, STING, protein degradation
- MeSH terms
- Cells, Cultured, DNA, Viral, Flow Cytometry, Herpes Labialis, Humans, Nuclear Proteins, Phosphoproteins, Signal Transduction, Polymerase Chain Reaction, Immediate-Early Proteins, Herpesvirus 1, Human, Fluorescent Antibody Technique, Indirect, Ubiquitin-Protein Ligases, Interferon Regulatory Factor-3
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