Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1
ABSTRACT 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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ABSTRACT: Cellular proteins called 'restriction factors' (RFs) form an important component of the innate immune response to viral replication. However, viruses have learned how to antagonize RFs through mechanisms that are specific for each virus. Here, we summarize the general hallmarks of RFs before going on to discuss the specific strategies recruited by some key RFs that strive to hold human CMV (HCMV) infection back, as well as the counter-restriction mechanisms employed by the virus to overcome this innate defense. Such RFs include the cellular constituents of nuclear domain 10 (ND10), and IFI16, a nuclear member of the PYHIN protein family. Viral regulatory proteins, such as IE1 or pp71, try to oppose the ND10-induced blockade of virus replication by either modifying or disrupting this RF. IFI16, on the other hand, inhibits virus DNA synthesis by downregulating the transcription of viral gene UL54; the intruding virus attempts to antagonize IFI16 by mislocalizing it from the nucleus to the cytoplasm via the action of viral protein UL97. Finally, we consider how Viperin, a RF initially thought to inhibit HCMV maturation late during infection, has actually been demonstrated to enhance virus maturation by increasing lipid metabolism and enhancing virus envelopment.Future Virology 05/2014; 9(5):499-511. DOI:10.2217/fvl.14.22 · 1.00 Impact Factor
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ABSTRACT: One of the first lines of defense of the host immune response to infection is upregulation of interferons, which play a vital role in triggering the early nonspecific antiviral state of the host. Interferons prompt the generation of numerous downstream products, known as interferon-stimulated genes (ISGs). One such ISG found to be either directly induced by type I, II, and III interferons or indirectly through viral infection is the 'virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible' protein, or viperin. Not only is viperin capable of combating a wide array of viral infections but its upregulation is also observed in the presence of endotoxins, various bacterial infections, or even in response to other immune stimuli, such as atherosclerotic lesions. Recent advances in the understanding of possible mechanisms of action of viperin involve, but are perhaps not limited to, interaction with farnesyl pyrophosphate synthase and disruption of lipid raft domains to prevent viral bud release, inhibition of hepatitis C virus secretory proteins, and coordination to lipid droplets and inhibition of viral replication. Unexpectedly, new insight into the human cytomegalovirus induction of this antiviral protein demonstrates that mitochondrial viperin plays a necessary and beneficial role for viral propagation.Biomolecular concepts 06/2012; 3(3):255-266. DOI:10.1515/bmc-2011-0057
Article: Characterisation of chicken viperin[Show abstract] [Hide abstract]
ABSTRACT: The identification of immune pathways that protect against pathogens may lead to novel molecular therapies for both livestock and human health. Interferon (IFN) is a major response pathway that stimulates multiple genes targeted towards reducing virus. Viperin is one such interferon stimulated gene (ISG) that helps protect mammals from virus and may be critical to protecting chickens in the same way. In chickens, ISGs are not generally well characterised and viperin, in concert with other ISGs, may be important in protecting against virus. Here we identify chicken viperin (ch-viperin) and show that ch-viperin is upregulated in response to viral signature molecules. We further show that viperin is upregulated in response to virus infection in vivo. This data will benefit investigators targeting the antiviral pathways in the chicken.Molecular Immunology 10/2014; 63(2). DOI:10.1016/j.molimm.2014.09.011 · 3.00 Impact Factor