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The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication.
- Source :
-
PLoS pathogens [PLoS Pathog] 2012 Jan; Vol. 8 (1), pp. e1002498. Date of Electronic Publication: 2012 Jan 26. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Animals
Chlorocebus aethiops
Cytomegalovirus Infections genetics
Cytomegalovirus Infections immunology
Cytomegalovirus Infections pathology
DNA, Viral genetics
DNA, Viral immunology
DNA-Directed DNA Polymerase genetics
DNA-Directed DNA Polymerase immunology
Embryo, Mammalian immunology
Embryo, Mammalian metabolism
Embryo, Mammalian pathology
Embryo, Mammalian virology
Fibroblasts immunology
Fibroblasts metabolism
Fibroblasts pathology
Fibroblasts virology
HEK293 Cells
Humans
Mice
Nuclear Proteins genetics
Phosphoproteins genetics
Response Elements physiology
Sp1 Transcription Factor genetics
Sp1 Transcription Factor immunology
Sp1 Transcription Factor metabolism
Vero Cells
Viral Proteins genetics
Viral Proteins immunology
Cytomegalovirus physiology
Cytomegalovirus Infections metabolism
DNA, Viral biosynthesis
DNA-Directed DNA Polymerase metabolism
Immunity, Innate physiology
Nuclear Proteins metabolism
Phosphoproteins metabolism
Viral Proteins metabolism
Virus Replication physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 22291595
- Full Text :
- https://doi.org/10.1371/journal.ppat.1002498