Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus
18 Dec 2001-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 98, Iss: 26, pp 15125-15130
TL;DR: The identification of a cytoplasmic antiviral protein that is induced by IFNs, by HCMV infection, and by the H CMV envelope protein, glycoprotein B (gB), which is named viperin (for virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible).
Abstract: Little is known about the mechanism by which IFNs inhibit human cytomegalovirus (HCMV) replication. Indeed, infection of fibroblasts with HCMV initiates the expression of a subset of type I IFN-inducible genes whose role in the infectious process is unclear. We describe here the identification of a cytoplasmic antiviral protein that is induced by IFNs, by HCMV infection, and by the HCMV envelope protein, glycoprotein B (gB). Stable expression of the protein in fibroblasts inhibits productive HCMV infection, down-regulating several HCMV structural proteins (gB, pp28, and pp65) known to be indispensable for viral assembly and maturation. We have named the protein viperin (for virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible). HCMV infection causes the redistribution of the induced viperin from its normal endoplasmic reticulum association, first to the Golgi apparatus and then to cytoplasmic vacuoles containing gB and pp28. Expression before HCMV infection reduces viperin redistribution from the endoplasmic reticulum to the Golgi apparatus and prevents vacuolar localization, perhaps reflecting the mechanism used by HCMV to evade the antiviral function.
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TL;DR: This review begins by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production and describes ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the Jak-STAT pathway.
Abstract: Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape.
2,207 citations
TL;DR: Applied aspects that arise from an increase in knowledge in this area are described, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
Abstract: The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.
1,564 citations
Cites background from "Viperin (cig5), an IFN-inducible an..."
...On the other hand, soluble HSV-1 gD (Ankel et al., 1998) and soluble HCMV gB (Boehme & Compton, 2004) induced IFN-b or IRF-3 activation in some cell types....
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...Interestingly, at higher m.o.i. with HCMV, NF-kB activation and IFN-a/b production were observed (Paladino et al., 2006)....
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...For example, to aid replication, the AdV E4orf3 protein reorganizes PML nuclear bodies into thread-like structures (Doucas et al., 1996; Stracker et al., 2005; Hoppe et al., 2006; Ullman et al., 2007); the ICP0 protein of HSV-1 has E3 ligase activity that induces the degradation of PML and SUMO-modified forms of Sp100 (reviewed by Hagglund & Roizman, 2004); EBV nuclear antigen 5 (EBNA5) interacts with Sp100A, but this may be to release PML-associated factors from PML nuclear bodies to aid viral gene expression (Ling et al., 2005); HCMV IE72 induces the loss of SUMO-modified forms of PML to disrupt PML nuclear bodies (Ahn & Hayward, 2000; Kang et al., 2006), and pp71 localizes to PML nuclear bodies to induce the degradation of hDaxx, which inhibits HCMV IE gene expression (Cantrell & Bresnahan, 2006; Preston & Nicholl, 2006; Saffert & Kalejta, 2006)....
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...At low m.o.i., HSV-1 and HCMV particles do not induce NF-kB in the absence of viral replication (Paladino et al., 2006), implying the existence of a signalling mechanism that activates IRF3, but not NF-kB....
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...In response to exposure to either human cytomegalovirus (HCMV) or HSV-1, human fibroblasts activate IRF-3 complex formation without new protein synthesis (Navarro et al., 1998; Mossman et al., 2001; Preston et al., 2001)....
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TL;DR: The goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.
Abstract: The family of interferon (IFN) proteins has now more than reached the potential envisioned by early discovering virologists: IFNs are not only antivirals with a spectrum of clinical effectiveness against both RNA and DNA viruses, but are also the prototypic biological response modifiers for oncology, and show effectiveness in suppressing manifestations of multiple sclerosis. Studies of IFNs have resulted in fundamental insights into cellular signalling mechanisms, gene transcription and innate and acquired immunity. Further elucidation of the multitude of IFN-induced genes, as well as drug development strategies targeting IFN production via the activation of the Toll-like receptors (TLRs), will almost certainly lead to newer and more efficacious therapeutics. Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.
1,069 citations
TL;DR: Some of the most potent antiviral effectors reinforce the system by further inducing IFN or ISGs, suggesting that some viruses may have evolved to co-opt IFN effectors for a survival advantage.
1,068 citations
Cites background from "Viperin (cig5), an IFN-inducible an..."
...However, viperin was originally identified as an antiviral effector that is highly induced in fibroblasts infected with human cytomegalovirus (HCMV) or treated with IFN [30]....
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TL;DR: It is reported that the RIG-I-like receptor (RLR) adaptor protein MAVS is located on peroxisomes and mitochondria and it is found thatperoxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state.
723 citations
Cites methods from "Viperin (cig5), an IFN-inducible an..."
...Cells were infected with reovirus, and extracts were examined at various times for expression of viperin, a well-charac- terized ISG (Chin and Cresswell, 2001; Severa et al., 2006)....
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...Cells were infected with reovirus, and extracts were examined at various times for expression of viperin, a well-characterized ISG (Chin and Cresswell, 2001; Severa et al., 2006)....
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References
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TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Abstract: Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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TL;DR: This work has identified a WD repeat host protein that was recruited to and actively retained on phagosomes by living, but not dead, mycobacteria, and this protein, termed TACO, represents a component of the phagosome coat that is normally released prior tophagosome fusion with or maturation into lysosomes.
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TL;DR: It is possible to identify and catalog the host cell genes whose mRNA levels change in response to a pathogen, and several of these mRNAs encode gene products that might play key roles in virus-induced pathogenesis, identifying them as intriguing targets for further study.
Abstract: Mechanistic insights to viral replication and pathogenesis generally have come from the analysis of viral gene products, either by studying their biochemical activities and interactions individually or by creating mutant viruses and analyzing their phenotype Now it is possible to identify and catalog the host cell genes whose mRNA levels change in response to a pathogen We have used DNA array technology to monitor the level of ≈6,600 human mRNAs in uninfected as compared with human cytomegalovirus-infected cells The level of 258 mRNAs changed by a factor of 4 or more before the onset of viral DNA replication Several of these mRNAs encode gene products that might play key roles in virus-induced pathogenesis, identifying them as intriguing targets for further study
457 citations
TL;DR: Investigating the assembly of HCMV by determining the intracellular trafficking of the abundant tegument protein pp150 (UL32) in productively infected human fibroblasts indicated that pp150 remained within the cytoplasm throughout the replicative cycle of H CMV and accumulated in a stable, juxtanuclear structure late in infection.
Abstract: The assembly of human cytomegalovirus (HCMV) is thought to be similar to that which has been proposed for alphaherpesviruses and involve envelopment of tegumented subviral particles at the nuclear membrane followed by export from the cell by a poorly defined pathway. However, several studies have shown that at least two tegument virion proteins remain in the cytoplasm during the HCMV replicative cycle, thereby suggesting that HCMV cannot acquire its final envelope at the nuclear envelope. We investigated the assembly of HCMV by determining the intracellular trafficking of the abundant tegument protein pp150 (UL32) in productively infected human fibroblasts. Our results indicated that pp150 remained within the cytoplasm throughout the replicative cycle of HCMV and accumulated in a stable, juxtanuclear structure late in infection. Image analysis using a variety of cell protein-specific antibodies indicated that the pp150-containing structure was not a component of the endoplasmic reticulum, (ER), ER-Golgi intermediate compartment, cis or medial Golgi, or lysosomes. Partial colocalization of the structure was noted with the trans-Golgi network, and it appeared to lie in close proximity to the microtubule organizing center. Two additional tegument proteins (pp28 and pp65) and three envelope glycoproteins (gB, gH, and gp65) localized in this same structure late infection. This compartment appeared to be relatively stable since pp150, pp65, and the processed form of gB could be coisolated following cell fractionation. Our findings indicated that pp150 was expressed exclusively within the cytoplasm throughout the infectious cycle of HCMV and that the accumulation of the pp150 in this cytoplasmic structure was accompanied by at least five other virion proteins. These results suggested the possibility that this virus-induced structure represented a cytoplasmic site of virus assembly.
359 citations
TL;DR: It is concluded that human cytomegalovirus induces interferon-responsive mRNAs, which accumulate after infection with virus that has been inactivated by treatment with UV light, indicating that the inducer is present in virions.
Abstract: We used differential display analysis to identify mRNAs that accumulate to enhanced levels in human cytomegalovirus-infected cells as compared with mock-infected cells. RNAs were compared at 8 hr after infection of primary human fibroblasts. Fifty-seven partial cDNA clones were isolated, representing about 26 differentially expressed mRNAs. Eleven of the mRNAs were virus-coded, and 15 were of cellular origin. Six of the partial cDNA sequences have not been reported previously. All of the cellular mRNAs identified in the screen are induced by interferon α. The induction in virus-infected cells, however, does not involve the action of interferon or other small signaling molecules. Neutralizing antibodies that block virus infection also block the induction. These RNAs accumulate after infection with virus that has been inactivated by treatment with UV light, indicating that the inducer is present in virions. We conclude that human cytomegalovirus induces interferon-responsive mRNAs.
307 citations