The Interferon-Inducible 204 Gene Is Transcriptionally Activated by Mouse Cytomegalovirus and Is Required for Its Replication

Rolle, S; Andrea, Marco De; Gioia, Daniela; Lembo, David; Hertel, Laura; Landolfo, Santo; Gariglio, Marisa

doi:10.1006/viro.2001.1021

Cited by 23 publications

(19 citation statements)

References 21 publications

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“…A p200 protein has previously been shown to play an important role during murine cytomegalovirus (MCMV) infection (35,70). Replication of MCMV is decreased in cells containing a dominant negative form of the murine p200 family member p204.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein

Cristea

Moorman

Terhune

et al. 2010

J Virol

144

181

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The human cytomegalovirus (HCMV) virion protein pUL83 (also termed pp65) inhibits the expression of interferon-inducible cellular genes. In this work we demonstrate that pUL83 is also important for efficient induction of transcription from the viral major immediate-early promoter. Infection with a mutant virus containing a premature translation termination codon in the UL83 open reading frame (ORF) (UL83Stop) resulted in decreased transcription from the major immediate-early promoter in a time-and multiplicitydependent manner. Expression of pUL83 alone is capable of transactivating the promoter in a reporter assay, and pUL83 associates with the promoter in infected cells. To investigate the mechanism by which the protein regulates the major immediate-early promoter, we utilized a mutant virus expressing an epitope-tagged pUL83 from its own promoter to identify protein binding partners for pUL83 during infection. We identified and confirmed the interaction of pUL83 with cellular IFI16 family members throughout the course of HCMV infection. pUL83 recruits IFI16 to the major immediate-early promoter, and IFI16 binding at the promoter is dependent upon the presence of pUL83. Consistent with the results obtained with the UL83Stop virus, infection of IFI16 knockdown cells with wild-type virus resulted in decreased levels of immediate-early transcripts compared to those of control cells. These data identify a previously unknown role for pUL83 in the initiation of the human cytomegalovirus gene expression cascade.Viral infection is marked by a race between the competing interests of the virus and the host cell. Efficient initiation of viral gene expression is critical to circumvent host defenses aimed at blocking viral gene expression. Human cytomegalovirus (HCMV), a betaherpesvirus encoding nearly 200 predicted proteins (57, 59), has evolved multiple means to evade the initial host cell response to infection. The first viral proteins expressed, the immediate-early proteins, play an important role in this process. Immediate-early proteins are detected in fibroblasts within 4 h of infection and thus are available to function at very early stages in the viral life cycle to block antiviral signaling events. For example, the IE1 protein binds to and inhibits STAT1 and STAT2 (64), two host cell proteins critical for the activation of interferon-inducible gene expression; and IE2 has also been implicated in regulation of transcription of antiviral genes (80). pTRS1 blocks the activation of protein kinase R (PKR), an important regulator of protein translation in response to innate immune signals (16,33,54,85), and pUS3 inhibits antigen presentation by infected cells by sequestering and degrading the major histocompatibility complex (MHC) class I heavy-chain complex (39,48,55).In addition to their role in subverting the host response to viral infection, immediate-early proteins are critical for the induction of viral gene expression. IE1 binds to and inhibits histone deacetylases (HDACs) to ensure a chromatin structure on viral...

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein

Cristea

Moorman

Terhune

et al. 2010

J Virol

144

181

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“…A key question that remains, however, concerns the mechanism(s) by which specific IFNinduced cellular genes have a proviral effect. One clue may come from models of mouse cytomegalovirus infection, in which a G 1 cell cycle arrest following IFN induction is essential for viral DNA replication (219,434).…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

309

367

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Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection

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“…The TRIF-dependent genes include IRF-7, Mx1, Mx2, ISG20, and IFI204, which have been implicated in the generation of antiviral immune responses or viral replication [30][31][32][33]. In addition, the genes encoding CXCL10, GARG16, Mx1, IFI204, and IRF-7 were previously shown to be expressed as part of a TLR3/TLR4-specific antiviral gene program of B lymphocytes [9].…”

Section: Fig 3 Effect Of Trif-deficiency On the Expression Of Ifnrementioning

confidence: 99%

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

et al. 2004

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Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-g (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIFdependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens. Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.

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The Interferon-Inducible 204 Gene Is Transcriptionally Activated by Mouse Cytomegalovirus and Is Required for Its Replication

Cited by 23 publications

References 21 publications

Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein

Human Cytomegalovirus pUL83 Stimulates Activity of the Viral Immediate-Early Promoter through Its Interaction with the Cellular IFI16 Protein

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

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