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Viperin: a Multifunctional, Interferon-Inducible Protein That Regulates Virus Replication

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Viperin: a Multifunctional, Interferon-Inducible Protein That Regulates Virus Replication Cell Host & Microbe Short Review Viperin: A Multifunctional, Interferon-Inducible Protein that Regulates Virus Replication Jun-Young Seo,1,2 Rakina Yaneva,1,2 and Peter Cresswell1,2,* 1Department of Immunobiology 2Howard Hughes Medical Institute Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8011, USA *Correspondence: [email protected] DOI 10.1016/j.chom.2011.11.004 Viperin is an interferon-inducible protein that inhibits the replication of a variety of viruses by apparently diverse mechanisms. In some circumstances, it also plays a role in intracellular signaling pathways. Its expression in mitochondria, revealed by infection with human cytomegalovirus, also affects cellular metabolic pathways. We review here the current status of our understanding of this unusual molecule. Introduction motif, and a C-terminal domain that is also highly conserved The first line of defense against viral infection is the interferon between species (Figure 1). The N-terminal domain contains (IFN) response, which triggers the induction of a broad array an amphipathic a helix. This sequence may also constitute of antiviral proteins. Although some IFN-inducible proteins, for a leucine zipper, but no zipper-like function, e.g., homodimeriza- example protein kinase R (PKR), the GTPase Mx1 (myxovirus tion, has been ascribed to it. Amphipathic a helices are known resistance 1), ribonuclease L (RNaseL), ISG15 (IFN-stimulated to bind membranes and induce membrane curvature (McMahon protein of 15 kDa), and IFIT (IFN-induced proteins with tetratri- and Gallop, 2005), and the N-terminal a helix is responsible for copeptide repeats), have been functionally well characterized viperin association with the cytosolic face of the endoplasmic as antiviral effectors (Daffis et al., 2010; Pichlmair et al., 2011; reticulum (ER) and also with lipid droplets (Hinson and Cress- Sadler and Williams, 2008), the functions of most IFN-inducible well, 2009a, 2009b). The interaction of viperin with the former proteins remain unexplored. Viperin (virus inhibitory protein, induces structural changes known as crystalloid ER, with endoplasmic reticulum-associated, interferon-inducible) is an closely stacked ER leaflets formed by viperin oligomerization IFN-inducible protein that has recently received increasing at the cytosolic surface. The amphipathic a helix is not neces- attention. It appears to have a number of functions, from being sary for viperin oligomerization and does not induce crystalloid an antiviral protein to modulating signaling events. Here, we ER when attached to the monomeric fluorescent reporter review these developments and attempt to provide a coherent protein dsRed (Hinson and Cresswell, 2009b). The central view of the properties of this unusual protein. domain (residues 71–182 of human viperin) shows significant homology with the MoA/PQQIII motif present in the ‘‘Radical Characterization of Viperin SAM’’ family of enzymes that use S-adenosylmethionine as a Viperin was identified as the product of an IFN-g-inducible gene cofactor, in which the CxxxCxxC motif is responsible for binding while analyzing the IFN-g response of human macrophages iron-sulfur clusters. Thus, viperin is also known as RSAD2 (Chin and Cresswell, 2001). It is identical to cig5 (cytomegalo- (radical SAM domain-containing 2). Recently, it has been shown virus-inducible gene 5), which was isolated by differential display that viperin can indeed bind Fe-S clusters (Duschene and Bro- analysis of primary fibroblasts infected with human cytomegalo- derick, 2010; Shaveta et al., 2010). Radical SAM enzymes virus (HCMV) (Zhu et al., 1997). Viperin is highly conserved in generally use the associated Fe-S cluster to generate a highly evolution. A homolog called BEST5 (bone-expressed sequence oxidizing deoxyadenosyl radical to mediate a variety of reac- tag 5) was described as an IFN-inducible gene expressed during tions. Although no specific enzyme activity has been ascribed rat osteoblast differentiation, and another called vig-1 (viral to viperin, the Fe-S binding motif is essential for its functional hemorrhagic septicemia virus [VHSV]-induced gene 1) was activities in hepatitis C virus (HCV) and HCMV infection (Jiang induced in rainbow trout leukocytes infected with VHSV, a fish et al., 2008; Seo et al., 2011). The role of the conserved rhabdovirus. It has since been cloned from species ranging C-terminal domain is unknown, but it might be involved in from the mouse to a variety of other fish. A number of experi- protein-protein interactions and/or substrate recognition ments involving either overexpression of viperin or its knock- required for mediating an enzyme activity. Consistent with down by short inhibitory RNAs in cell lines have indicated that this, an aromatic amino acid residue at the C terminus of viperin the protein possesses antiviral activity against a variety of RNA is required for its antiviral activity against HCV (Jiang et al., and DNA viruses (see below). 2008). Human viperin is composed of 361 amino acids with a molec- ular mass of approximately 42 kDa. It is composed of three Regulation of Viperin Expression distinct domains, an N-terminal domain, with length and se- Viperin is induced in a variety of cell types by type I (a and b), II quence variability between species, a conserved central domain (g), and III (l) IFNs, by double-stranded (ds) B-form DNA, the that contains three cysteine residues organized in a CxxxCxxC dsRNA analog poly I:C, lipopolysaccharide (LPS), and infection 534 Cell Host & Microbe 10, December 15, 2011 ª2011 Elsevier Inc. Cell Host & Microbe Short Review Figure 1. Viperin Is Evolutionarily Highly Conserved and Contains an N-Terminal Amphipathic a Helix and Binds Fe-S Clusters (A) The sequences for human, mouse, rat, and fish viperins are shown, and conserved amino acid residues are shaded in blue. The amphipathic a helix, shared by the mammalian species, extends from residues 9–42. The CxxxCxxC motif, responsible for coordinating the binding of Fe4-S4 clusters, is embedded in a conserved region extending from residues 71–182 that identifies viperin as a member of the MoaA/PDQQIII family of radical SAM proteins. (B) Schematic diagram of viperin’s known domains. The N-terminal domain is required for its localization to the cytosolic face of the ER and lipid droplets. The central domain which contains an Fe-S cluster binding motif (CxxxCxxC) is essential for its functional activities in hepatitis C virus (HCV) and human cytomegalovirus (HCMV) infection. The C-terminal domain (residues 183– 361) is highly conserved but no functions have yet been ascribed to it. Some viruses, such as HCMV and vesicular stomatitis virus (VSV), directly induce viperin independently of IFN production (Boehme et al., 2004; Boudinot et al., 2000; Chin and Cresswell, 2001; Zhu et al., 1997). In the former case, this may be mediated by the HCMV membrane glycoprotein, glycoprotein B (gB) (Boehme et al., 2004). IFN-independent viperin induction is directly regulated by IRF1 or IRF3 (DeFilippis et al., 2006; Stirnweiss et al., 2010). It is known that IRF3 is able to discriminate between different IFN-stimulated responsive element (ISRE)-containing genes that directly respond to virus infection (Grandvaux et al., 2002). Both human and mouse viperin promoters have two ISREs that are directly responsive. A recent study has shown that the IFN-independent viperin induction by VSV appears to use IRFs activated by the mito- chondrial anti viral signaling protein (MAVS), in this case localized to peroxisomes rather than mitochondria. Upon viral infection, peroxi- somal MAVS induces rapid and transient with a range of viruses. While IFN-g strongly induces viperin IFN-independent viperin expression, whereas mitochondrial expression in primary macrophages, IFN-a and IFN-b are more MAVS activates IFN-mediated viperin expression with delayed effective in inducing its expression in the majority of cell types. kinetics (Dixit et al., 2010). The IFN-mediated viperin gene Viperin induction by poly I:C, LPS, dsDNA, and many viruses, expression is regulated by ISGF3, and the IFN-independent for example Sendai virus, Sindbis virus, and Pseudorabies virus viperin gene expression is regulated by IRF1 and IRF3, as (PrV), is mediated by the classical IFN-stimulated gene (ISG) described above. The latter also play a direct role in promoting induction pathways (Bowie and Unterholzner, 2008). IFN- the peroxisomal MAVS signaling pathway. b synthesis is induced by interferon regulatory factors IRF3 and IRF7, which are activated by pattern recognition receptors Antiviral Functions of Viperin (PRRs), such as the Toll-like receptors TLR3 and TLR4, the Viperin has been reported to inhibit a broad spectrum of DNA cytosolic retinoic acid inducible gene I (RIG-I)-like receptors and RNA viruses, including herpesviruses (HCMV), flaviviruses (RLRs), and cytosolic DNA sensor(s). The secreted IFN-b binds (HCV, West Nile virus [WNV], and Dengue virus), an alphavirus to the type I IFN receptor (IFNR) on the cell surface in an auto- (Sindbis virus), an orthomyxovirus (Influenza A virus), a para- crine/paracrine manner. This induces the formation of the myxovirus (Sendai virus), a rhabdovirus (VSV), and a retrovirus IFN-stimulated gene factor 3 (ISGF3) complex, which binds to (HIV-1) (Chin and Cresswell, 2001; Jiang et al., 2008, 2010; Riv- the viperin promoter and induces its expression (Figure 2). ieccio et al., 2006; Stirnweiss et al., 2010; Wang et al., 2007; Cell Host & Microbe 10, December 15, 2011 ª2011 Elsevier Inc. 535 Cell Host & Microbe Short Review Figure 3. The Effects of Viperin Expression on Cellular Processes Viperin association with the cytosolic face of the ER reduces the secretion rate of soluble molecules, a function ascribed to the N-terminal amphipathic a helix. The a helix also can target viperin to lipid droplets, where an activity dependent on Fe-S cluster binding may affect the replication of viruses such as Figure 2. Regulation of Viperin Expression HCV. Viperin expression also affects lipid raft formation, reducing membrane Viperin induction is mediated by both the classical IFN-stimulated gene fluidity and inhibiting the budding of influenza A virus.
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