The Intracellular DNA Sensor IFI16 Gene Acts as Restriction Factor for Human Cytomegalovirus Replication
Open accessAbstract
Human interferon (IFN)-inducible IFI16 protein, an innate immune sensor of intracellular DNA, modulates various cell functions, however, its role in regulating virus growth remains unresolved. Here, we adopt two approaches to investigate whether IFI16 exerts pro- and/or anti-viral actions. First, the IFI16 gene was silenced using specific small interfering RNAs (siRNA) in human embryo lung fibroblasts (HELF) and replication of DNA and RNA viruses evaluated. IFI16-knockdown resulted in enhanced replication of Herpesviruses, in particular, Human Cytomegalovirus (HCMV). Consistent with this, HELF transduction with a dominant negative form of IFI16 lacking the PYRIN domain (PYD) enhanced the replication of HCMV. Second, HCMV replication was compared between HELFs overexpressing either the IFI16 gene or the LacZ gene. IFI16 overexpression decreased both virus yield and viral DNA copy number. Early and late, but not immediate-early, mRNAs and proteins were strongly down-regulated, thus IFI16 may exert its antiviral effect by impairing viral DNA synthesis. Constructs with the luciferase reporter gene driven by deleted or site-specific mutated forms of the HCMV DNA polymerase (UL54) promoter demonstrated that the inverted repeat element 1 (IR-1), located between -54 and -43 relative to the transcription start site, is the target of IFI16 suppression. Indeed, electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated that suppression of the UL54 promoter is mediated by IFI16-induced blocking of Sp1-like factors. Consistent with these results, deletion of the putative Sp1 responsive element from the HCMV UL44 promoter also relieved IFI16 suppression. Together, these data implicate IFI16 as a novel restriction factor against HCMV replication and provide new insight into the physiological functions of the IFN-inducible gene IFI16 as a viral restriction factor.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IFI16 interacts with and inhibits SP1 interaction to its cognate binding sites on DNA.
“On the other hand, IFI16 interacts with and inhibits SP1 interaction to its cognate binding sites on DNA.46”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Interferon-inducible antiviral effectors
Sadler, A. J., & Williams, B. R. G. (2008) · Nature Reviews Immunology · doi:10.1038/nri2314 · Cited by 2,160 · see citing works
IFI16 is an innate immune sensor for intracellular DNA
Unterholzner, L., Keating, S. E., Baran, M., Horan, K. A., Jensen, S. B., Sharma, S., Sirois, C. M., Jin, T., Latz, E., Xiao, T. S., et al. (2010) · Nature Immunology · doi:10.1038/ni.1932 · Cited by 1,643 · see citing works
Kerur, N., Veettil, M. V., Sharma-Walia, N., Bottero, V., Sadagopan, S., Otageri, P., & Chandran, B. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.04.008 · Cited by 702 · see citing works
Intrinsic immunity: a front-line defense against viral attack
Bieniasz, P. D. (2004) · Nature Immunology · doi:10.1038/ni1125 · Cited by 450 · see citing works
Interferons and viral infections
Fensterl, V., & Sen, G. C. (2009) · BioFactors · doi:10.1002/biof.6 · Cited by 396 · see citing works
Sequestration and Inhibition of Daxx-Mediated Transcriptional Repression by PML
Li, H., Leo, C., Zhu, J., Wu, X., O’Neil, J., Park, E., & Chen, J. D. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.5.1784-1796.2000 · Cited by 364 · see citing works
Landolfo, S., Gariglio, M., Gribaudo, G., et al. (2003) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(03)00034-2 · Cited by 358 · see citing works
Self-citationRecognition of herpesviruses by the innate immune system
Paludan, S. R., Bowie, A., Horan, K., & Fitzgerald, K. A. (2011) · Nature reviews. Immunology · doi:10.1038/nri2937 · Cited by 353 · see citing works
Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease
Britt, W. J. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-77349-8_23 · Cited by 346 · see citing works
APOBEC proteins and intrinsic resistance to HIV-1 infection
Malim, M. H. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0185 · Cited by 276 · see citing works
Hollenbach, A. D., McPherson, C. J., Mientjes, E., Iyengar, R. V., & Grosveld, G. C. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.16.3319 · Cited by 260 · see citing works
Tavalai, N., Papior, P., Rechter, S., Leis, M., & Stamminger, T. (2006) · Journal of Virology · doi:10.1128/jvi.00743-06 · Cited by 210 · see citing works
Activation of host pattern recognition receptors by viruses
Brennan, K., & Bowie, A. (2010) · Current Opinion in Microbiology · doi:10.1016/j.mib.2010.05.007 · Cited by 176 · see citing works
New insights into the role of the subnuclear structure ND10 for viral infection
Tavalai, N., & Stamminger, T. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.08.004 · Cited by 171 · see citing works
The HIN-200 family: More than interferon-inducible genes?
Ludlow, L. E. A., Johnstone, R. W., & Clarke, C. J. P. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.03.032 · Cited by 170 · see citing works
Cristea, I. M., Moorman, N. J., Terhune, S. S., Cuevas, C. D., O'Keefe, E. S., Rout, M. P., Chait, B. T., & Shenk, T. (2010) · Journal of Virology · doi:10.1128/jvi.00139-10 · Cited by 155 · see citing works
HCMV Spread and Cell Tropism are Determined by Distinct Virus Populations
Scrivano, L., Sinzger, C., Nitschko, H., Koszinowski, U. H., & Adler, B. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1001256 · Cited by 150 · see citing works
Murgue, B., Roche, C., Chungue, E., & Deparis, X. (2000) · Journal of Medical Virology · doi:10.1002/(sici)1096-9071(200004)60:4 · Cited by 149 · see citing works
Revello, M. G., & Gerna, G. (2010) · Reviews in Medical Virology · doi:10.1002/rmv.645 · Cited by 145 · see citing works
Quantitative Analysis of Cytomegalovirus Load Using a Real-Time PCR Assay
田中, 直. (2001) · Medical Entomology and Zoology · doi:10.11501/3181359 · Cited by 143 · see citing works
Requirement of IFI16 for the Maximal Activation of p53 Induced by Ionizing Radiation
Fujiuchi, N., Aglipay, J. A., Ohtsuka, T., Maehara, N., Sahin, F., Su, G. H., Lee, S. W., & Ouchi, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400344200 · Cited by 102 · see citing works
Innate immune sensing of DNA viruses
Rathinam, V. A. K., & Fitzgerald, K. A. (2011) · Virology · doi:10.1016/j.virol.2011.02.003 · Cited by 102 · see citing works
Interferon-Inducible Protein 16: Insight into the Interaction with Tumor Suppressor p53
Liao, J. C. C., Lam, R., Brázda, V., Duan, S., Ravichandran, M., Ma, J., Xiao, T., Tempel, W., Zuo, X., Wang, Y., et al. (2011) · Structure · doi:10.1016/j.str.2010.12.015 · Cited by 92 · see citing works
The Human Interferon-inducible Protein, IFI 16, Is a Repressor of Transcription
Johnstone, R. W., Kerry, J. A., & Trapani, J. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.27.17172 · Cited by 81 · see citing works
Leach, F. S., & Mocarski, E. S. (1989) · Journal of Virology · doi:10.1128/jvi.63.4.1783-1791.1989 · Cited by 74 · see citing works
Kerry, J. A., Priddy, M. A., Jervey, T. Y., et al. (1996) · Journal of Virology · doi:10.1128/jvi.70.1.373-382.1996 · Cited by 71 · see citing works
Strang, B. L., Boulant, S., & Coen, D. M. (2009) · Journal of Virology · doi:10.1128/jvi.01510-09 · Cited by 71 · see citing works
Caposio, P., Gugliesi, F., Zannetti, C., Sponza, S., Mondini, M., Médico, E., Hiscott, J. B., Young, H. A., Gribaudo, G., Gariglio, M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701846200 · Cited by 68 · see citing works
Self-citationCell Cycle Arrest by Human Cytomegalovirus 86-kDa IE2 Protein Resembles Premature Senescence
Noris, E., Zannetti, C., Demurtas, A., Sinclair, J. H., Andrea, M. D., Gariglio, M., & Landolfo, S. (2002) · Journal of Virology · doi:10.1128/jvi.76.23.12135-12148.2002 · Cited by 62 · see citing works
Self-citationSensing Cytoplasmic Danger Signals by the Inflammasome
Alnemri, E. S. (2010) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9419-0 · Cited by 61 · see citing works
Adler, M., Tavalai, N., Müller, R., et al. (2011) · Journal of General Virology · doi:10.1099/vir.0.030981-0 · Cited by 59 · see citing works
Subversion of Cell Cycle Regulatory Pathways
Sánchez, V., & Spector, D. H. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-77349-8_14 · Cited by 58 · see citing works
Gugliesi, F., Mondini, M., Ravera, R., Robotti, A., Andrea, M. D., Gribaudo, G., Gariglio, M., & Landolfo, S. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0904507 · Cited by 56 · see citing works
Self-citationThe Multifaceted Interferon-Inducible p200 Family Proteins: From Cell Biology to Human Pathology
Gariglio, M., Mondini, M., Andrea, M. D., & Landolfo, S. (2011) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2010.0106 · Cited by 55 · see citing works
Self-citationIsomura, H., Stinski, M. F., Kudoh, A., Murata, T., Nakayama, S., Sato, Y., Iwahori, S., & Tsurumi, T. (2007) · Journal of Virology · doi:10.1128/jvi.01917-07 · Cited by 53 · see citing works
Kerry, J. A., Priddy, M. A., & Stenberg, R. M. (1994) · Journal of Virology · doi:10.1128/jvi.68.7.4167-4176.1994 · Cited by 51 · see citing works
Luu, P., & Flores, O. A. (1997) · Journal of Virology · doi:10.1128/jvi.71.9.6683-6691.1997 · Cited by 43 · see citing works
Revello, M. G., Lilleri, D., Zavattoni, M., et al. (2001) · The Journal of Infectious Diseases · doi:10.1086/323425 · Cited by 41 · see citing works
Gribaudo, G., Riera, L., Rudge, T. L., et al. (2002) · Journal of General Virology · doi:10.1099/0022-1317-83-12-2983 · Cited by 38 · see citing works
Self-citationLuganini, A., Caposio, P., Landolfo, S., et al. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00987-07 · Cited by 38 · see citing works
Self-citationPYHIN proteins: center stage in DNA sensing
Goubau, D., Rehwinkel, J., & Sousa, C. R. E. (2010) · Nature Immunology · doi:10.1038/ni1110-984 · Cited by 37 · see citing works
Baggetta, R., Andrea, M. D., Gariano, G. R., Mondini, M., Rittà, M., Caposio, P., Cappello, P., Giovarelli, M., Gariglio, M., & Landolfo, S. (2010) · European Journal of Immunology · doi:10.1002/eji.200939995 · Cited by 35 · see citing works
Self-citationIsomura, H., Stinski, M. F., Kudoh, A., Nakayama, S., Iwahori, S., Sato, Y., & Tsurumi, T. (2007) · Journal of Virology · doi:10.1128/jvi.00089-07 · Cited by 32 · see citing works
Wu, J., O'Neill, J. P., & Barbosa, M. S. (1998) · Journal of Virology · doi:10.1128/jvi.72.1.236-244.1998 · Cited by 31 · see citing works
IFI16 and NM23 bind to a common DNA fragment both in the P53 and the cMYC gene promoters
Egistelli, L., Chichiarelli, S., Gaucci, E., et al. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22053 · Cited by 25 · see citing works
Rolle, S., Andrea, M. D., Gioia, D. M., et al. (2001) · Virology · doi:10.1006/viro.2001.1021 · Cited by 24 · see citing works
Azzimonti, B., Dell’Oste, V., Borgogna, C., Mondini, M., Gugliesi, F., Andrea, M. D., Chiorino, G., Scatolini, M., Ghimenti, C., Landolfo, S., et al. (2009) · Virology · doi:10.1016/j.virol.2009.03.033 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [2]Mocarski ES 2006 Cytomegaloviruses. Knipe InDM Howley PM Philadelphia Lippincott Williams & Wilkins 2701 2772
Cited by
Sorted by citations
Interferon-Stimulated Genes: What Do They All Do?
Schoggins, J. W. (2019) · Annual Review of Virology · doi:10.1146/annurev-virology-092818-015756 · Cited by 1,036 · see citing works
IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV
Monroe, K. M., Yang, Z., Johnson, J. R., Geng, X., Doitsh, G., Krogan, N. J., & Greene, W. C. (2014) · Science · doi:10.1126/science.1243640 · Cited by 511 · see citing works
STING and the innate immune response to nucleic acids in the cytosol
Burdette, D. L., & Vance, R. E. (2013) · Nature Immunology · doi:10.1038/ni.2491 · Cited by 501 · see citing works
Johnson, K. E., Chikoti, L., & Chandran, B. (2013) · Journal of Virology · doi:10.1128/jvi.00082-13 · Cited by 271 · see citing works
Human Cytomegalovirus Tegument Protein pUL83 Inhibits IFI16-Mediated DNA Sensing for Immune Evasion
Li, T., Chen, J., & Cristea, I. M. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.10.007 · Cited by 226 · see citing works
APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease
Vélez, J. I., Lopera, F., Sepulveda-Falla, D., Patel, H. R., Johar, A. S., Chuah, A., Tobón, C., Rivera, D., Villegas, A., Cai, Y., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.177 · Cited by 111 · see citing works
Cuchet-Lourenço, D., Anderson, G., Sloan, E., Orr, A., & Everett, R. D. (2013) · Journal of Virology · doi:10.1128/jvi.02474-13 · Cited by 98 · see citing works
Diner, B. A., Lum, K. K., Javitt, A., & Cristea, I. M. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.047068 · Cited by 93 · see citing works
IFI16: At the Interphase between Innate DNA Sensing and Genome Regulation
Jakobsen, M. R., & Paludan, S. R. (2014) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2014.06.004 · Cited by 72 · see citing works
Al-Ghamdi, M., Al-Ayadhi, L., & El-Ansary, A. (2014) · BMC Neuroscience · doi:10.1186/1471-2202-15-34 · Cited by 25 · see citing works
- Authors
- Gariano, G. R., Dell'Oste, V., Bronzini, M., Gatti, D., Luganini, A., De Andrea, M., Gribaudo, G., Gariglio, M., & Landolfo, S.
- Affiliations
- University of Turin (IT)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Corresponding author
- Landolfo, Santo
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-01-26
- Volume
- 8
- Issue
- 1
- Pages
- e1002498
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3266931
- OpenAlex
- W2074012862
- Cited by
- 227
- References
- 47
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 6 · 2022: 18 · 2021: 15 · 2020: 21 · 2019: 21 · 2018: 15 · 2017: 14 · 2016: 24 · 2015: 19 · 2014: 20 · 2013: 23 · 2012: 5
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN2007, PRIN 2008)
- Regione Piemonte
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Keywords
- IFI16, human cytomegalovirus, viral restriction factors, antiviral innate immunity, herpesvirus replication, pyrin domain, Sp1, viral DNA replication, interferon-stimulated genes
- MeSH terms
- Animals, Chlorocebus aethiops, Cytomegalovirus Infections, Cytomegalovirus, DNA-Directed DNA Polymerase, DNA, Viral, Embryo, Mammalian, Fibroblasts, Humans, Immunity, Innate, Nuclear Proteins, Phosphoproteins, Vero Cells, Viral Proteins, Virus Replication, Sp1 Transcription Factor, Response Elements, Mice, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
