Toll-like Receptor-dependent and -independent Viperin Gene Expression and Counter-regulation by PRDI-binding Factor-1/BLIMP1

Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2006; 281(36):26188-95. DOI: 10.1074/jbc.M604516200
Source: PubMed


Here we identify Viperin as a highly inducible gene in response to lipopolysaccharide (LPS), double-stranded RNA (poly(I-C)) or Sendai virus (SV). The only known function of Viperin relates to its ability to inhibit human Cytomegalovirus replication. Very little data are available on the regulation of this gene. In silico analysis of the promoter identified two interferon (IFN)-stimulated response elements (ISRE), which in other genes bind IRF3 or the IFN-stimulated gene factor-3 (ISGF3) complex. LPS and poly(I-C) induce very high levels of Viperin in wild type cells but not in cells deficient in TRIF, TBK1, IRF3, or the type I IFNalpha/betaR. SV-induced Viperin gene expression was mediated independently of Toll-like receptor (TLR) signaling by retinoic acid-inducible gene (RIG-I) and the downstream adapter, mitochondrial anti-viral signaling (MAVS). Virus-induced Viperin expression was not attenuated in macrophages deficient in either TBK1 or IKKepsilon alone. Moreover, IRF3-deficient, but not IFNalpha/betaR deficient, macrophages still induced Viperin in response to SV. Promoter reporter studies combined with DNA immunoprecipitation assays identified the ISGF3 complex as the key regulator of Viperin gene expression. Moreover, positive regulatory domain I-binding factor 1 (PRDI-BF1, also called BLIMP1) binds the ISRE sites and competes with ISGF3 binding in a virus inducible manner to inhibit Viperin transcription. Collectively, these studies identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1.

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    • "These in turn are able to activate interferon regulatory factors IRF3 and IRF7 to produce IFN-β, which is able to act in both a paracrine manner and an autocrine manner to bind the cell surface type I IFN receptor and initiate a signaling cascade that culminates in the formation of the ISG factor 3 (ISGF3), which is able to bind the viperin promoter and induce expression. Viperin has been previously demonstrated to be very tightly regulated by ISGF3, with counter-regulation exerted by the PRDI-binding factor-1 (BLIMP-1) [15]; however, more recent work by Xu et al. has indicated that the transcription factor promyelocytic leukemia zinc finger protein (PLZF) is essential for IFN-regulated viperin expression [17]. IFN stimulates an association of PLZF with promyelocytic leukemia protein and histone deacetylase 1 to induce a specific subset of ISGs, including viperin. "
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    ABSTRACT: Viral infection of the cell is able to initiate a signaling cascade of events that ultimately attempts to limit viral replication and prevent escalating infection through expression of host antiviral proteins. Recent work has highlighted the importance of the host antiviral protein viperin in this process, with its ability to limit a large variety of viral infections as well as play a role in the production of type I interferon and the modulation of a number of transcription factor binding sites. Viperin appears to have the ability to modulate varying conditions within the cell as well as interfere with proviral host proteins in its attempts to create an unfavourable environment for viral replication. The study of the mechanistic actions of viperin has come a long way in recent years, describing important functional domains of the protein for its antiviral and immune modulator actions as well as demonstrating its role as a member of the radical SAM enzyme family. However, despite the rapid expansion of knowledge regarding the functions of this highly conserved and ancient antiviral protein, there still remains large gaps in our understanding of the precise mechanisms at play for viperin to exert such a wide variety of roles within the cell.
    Full-text · Article · Oct 2013 · Journal of Molecular Biology
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    • "To exert their antimicrobial activity, IFNs modulate the expression of hundreds of IFN-stimulated genes (Katze et al. 2002). One such gene, encoding viperin, is evolutionarily conserved and found to be highly upregulated in response to bacterial lipopolysaccharide (LPS), doublestranded DNA and RNA analogs, and infection with various viruses (Boudinot et al. 2000, Chan et al. 2008, Helbig et al. 2005, Olofsson et al. 2005, Severa et al. 2006). Viperin possesses antiviral activity against a range of viruses including HCV, influenza virus, human immunodeficiency virus, Dengue virus, human cytomegalovirus, and alphaviruses (Fitzgerald 2011 and references therein). "
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    ABSTRACT: Lipid droplets (LDs) are neutral lipid storage organelles ubiquitous to eukaryotic cells. It is increasingly recognized that LDs interact extensively with other organelles and that they perform functions beyond passive lipid storage and lipid homeostasis. One emerging function for LDs is the coordination of immune responses, as these organelles participate in the generation of prostaglandins and leukotrienes, which are important inflammation mediators. Similarly, LDs are also beginning to be recognized as playing a role in interferon responses and in antigen cross presentation. Not surprisingly, there is emerging evidence that many pathogens, including hepatitis C and Dengue viruses, Chlamydia, and Mycobacterium, target LDs during infection either for nutritional purposes or as part of an anti-immunity strategy. We here review recent findings that link LDs to the regulation and execution of immune responses in the context of host-pathogen interactions.
    Full-text · Article · May 2012 · Annual Review of Cell and Developmental Biology
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    • "Viperin expression is highly induced by both type I and II IFNs in response to lipopolysaccharide and dsRNA (Fitzgerald, 2011), and its expression is regulated by the IFN-stimulated gene factor-3 complex (Chin & Cresswell, 2001; Severa et al., 2006). Upon synthesis, viperin localizes to the cytoplasmic face of the endoplasmic reticulum via its N-terminal amphipathic a-helix (Hinson & Cresswell, 2009; Wang et al., 2007). "
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    ABSTRACT: Influenza A virus has caused a number of pandemics in past decades, including the recent H1N1-2009 pandemic. Viperin is an interferon (IFN)-inducible protein of innate immunity, and acts as a broad-spectrum antiviral protein. We explored the antiviral activities and mechanisms of viperin during influenza virus (IFV) infection in vitro and in vivo. Wild-type (WT) HeLa and viperin-expressing HeLa cells were infected with influenza A/WSN/33/H1N1 (WSN33) virus, and subjected to virological, light and electron microscopic analyses. Viperin expression reduced virus replication and titres, and restricted viral budding. Young and old viperin-knockout (KO) mice and WT control animals were challenged with influenza WSN33 at lethal doses of 10(3) and 10(4) p.f.u. via the intratracheal route. Lungs were subjected to histopathological, virological and molecular studies. Upon lethal IFV challenge, both WT and KO mice revealed similar trends of infection and recovery with similar mortality rates. Viral quantification assay and histopathological evaluation of lungs from different time points showed no significant difference in viral loads and lung damage scores between the two groups of mice. Although the in vitro studies demonstrated the ability of viperin to restrict influenza H1N1 virus replication, the viperin-deficient mouse model indicated that absence of viperin enhanced neither the viral load nor pulmonary damage in the lungs of infected mice. This may be due to the compensation of IFN-stimulated genes in the lungs and/or the influenza non-structural protein 1-mediated IFN antagonism dampening the IFN response, thereby rendering the loss of viperin insignificant. Nevertheless, further investigations that exploit the antiviral mechanisms of viperin as prophylaxis are still warranted.
    Full-text · Article · Feb 2012 · Journal of General Virology
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