Cited by 424interferon and immune responsesHerpesvirus Infections and TreatmentsImmune Response and Inflammation

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Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein

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Orzalli, Megan H., DeLuca, Neal A., Knipe, David M.·2012·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1211302109PMC PMC3497734

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Abstract

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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Authors: Orzalli, M. H., DeLuca, N. A., & Knipe, D. M.
Affiliations: Harvard University (US)
University of Pittsburgh (US)
Corresponding author: Knipe, David M.
ORCID: Orzalli, Megan H.
DeLuca, Neal A.
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
DOI: 10.1073/pnas.1211302109
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 › Infectious Diseases › 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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Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein

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