Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16
Open accessAbstract
Detection of pathogenic nucleic acids is essential for mammalian innate immunity. IFN-inducible protein IFI16 has emerged as a critical sensor for detecting pathogenic DNA, stimulating both type I IFN and proinflammatory responses. Despite being predominantly nuclear, IFI16 can unexpectedly sense pathogenic DNA in both the cytoplasm and the nucleus. However, the mechanisms regulating its localization and sensing ability remain uncharacterized. Here, we propose a two-signal model for IFI16 sensing. We first identify an evolutionarily conserved multipartite nuclear localization signal (NLS). Next, using FISH and immunopurification, we demonstrate that IFI16 detects HSV-1 DNA primarily in the nucleus, requiring a functional NLS. Furthermore, we establish a localization-dependent IFN-β induction mediated by IFI16 in response to HSV-1 infection or viral DNA transfection. To identify mechanisms regulating the secondary cytoplasmic localization, we explored IFI16 posttranslation modifications. Combinatorial MS analyses identified numerous acetylations and phosphorylations on endogenous IFI16 in lymphocytes, in which we demonstrate an IFI16-mediated IFN-β response. Importantly, the IFI16 NLS was acetylated in lymphocytes, as well as in macrophages. Mutagenesis and nuclear import assays showed that NLS acetylations promote cytoplasmic localization by inhibiting nuclear import. Additionally, broad-spectrum deacetylase inhibition triggered accumulation of cytoplasmic IFI16, and we identify the acetyltransferase p300 as a regulator of IFI16 localization. Collectively, these studies establish acetylation as a molecular toggle of IFI16 distribution, providing a simple and elegant mechanism by which this versatile sensor detects pathogenic DNA in a localization-dependent manner.
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Two acetylations within the nuclear localization signal of IFI16 modulate its nuclear-cytoplasmic distribution, expanding its immunosurveillance to both subcellular compartments.
“Using AP-MS, we identified two acetylations within its nuclear localization signal that modulate IFI16 nuclear-cytoplasmic distribution, effectively expanding its range of immunosurveillance to both subcellular compartments (71).”
From The Impact of Mass Spectrometry–Based Proteomics on Fundamental Discoveries in Virology (2014) · cites this paper as [71]
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 [71]
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Self-citation
- Authors
- Li, T., Diner, B. A., Chen, J., & Cristea, I. M.
- Affiliations
- Princeton University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-06-12
- Volume
- 109
- Issue
- 26
- Pages
- 10558-10563
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3387042
- OpenAlex
- W2105121872
- Cited by
- 297
- References
- 36
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 14 · 2023: 11 · 2022: 22 · 2021: 24 · 2020: 19 · 2019: 23 · 2018: 25 · 2017: 17 · 2016: 24 · 2015: 32 · 2014: 35 · 2013: 26 · 2012: 6
- FWCI
- 13.79
- 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
- Princeton University
- Medizinischen Hochschule Hannover
- National Institutes of Health
- National Institute on Drug Abuse (DP1DA026192)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- IFI16, acetylation, post-translational modification, nuclear localization signal, cytoplasmic localization, DNA sensing, innate immunity, herpes simplex virus type 1, interferon-beta induction, P300, nuclear import, lymphocytes, macrophages, type I interferon
- MeSH terms
- Acetylation, Amino Acid Sequence, Animals, DNA, DNA, Viral, Humans, Molecular Sequence Data, Nuclear Proteins, Phosphoproteins, Phosphorylation, Sequence Homology, Amino Acid, In Situ Hybridization, Fluorescence, Nuclear Localization Signals
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