The Antiviral Cytomegalovirus Inducible Gene 5/Viperin Is Expressed in Atherosclerosis and Regulated by Proinflammatory Agents

Olofsson, Peder S.; Jatta, Ken; Wågsäter, Dick; Gredmark, Sara; Hedin, Ulf; Paulsson-Berne, Gabrielle; Söderberg‐Nauclér, Cecilia; Hansson, Göran K.; Sirsjö, Allan

doi:10.1161/01.atv.0000170130.85334.38

Cited by 52 publications

(52 citation statements)

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“…1,2 In the following studies using oligonucleotide microarray chip assays, viperin has been recognized as a highly inducible candidate gene in response to a wide range of viruses and microbial products such as LPS and double-stranded RNA, 3,4 implying that viperin is an important component of innate immunity to diverse pathogens. Viperin induction upon stimulation has been reported in human fetal astrocytes, 5 fibroblasts, Huh-7 and HepG2 cells 6,7 in vitro, and in disease conditions such as vascular cells of atherosclerosis 8 and liver tissue of patients with chronic hepatitis C. 3 Nevertheless, the cell types that are capable of producing viperin are still enigmatic, and the functions of viperin other than its antiviral activity have remained unexplored.…”

Section: Introductionmentioning

confidence: 99%

Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1

Qiu

Cresswell

Chin

2009

Blood

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IntroductionViperin (virus inhibitory protein, endoplasmic reticulumassociated, interferon-inducible) was first cloned from interferontreated human macrophages, 1 and identified as an antiviral protein that is protective against human cytomegalovirus and influenza A virus. 1,2 In the following studies using oligonucleotide microarray chip assays, viperin has been recognized as a highly inducible candidate gene in response to a wide range of viruses and microbial products such as LPS and double-stranded RNA, 3,4 implying that viperin is an important component of innate immunity to diverse pathogens. Viperin induction upon stimulation has been reported in human fetal astrocytes, 5 fibroblasts, Huh-7 and HepG2 cells 6,7 in vitro, and in disease conditions such as vascular cells of atherosclerosis 8 and liver tissue of patients with chronic hepatitis C. 3 Nevertheless, the cell types that are capable of producing viperin are still enigmatic, and the functions of viperin other than its antiviral activity have remained unexplored.In order to delineate the physiologic role of viperin in the immune system, a mouse model defective in viperin was generated by gene targeting. We assessed here whether viperin deficiency affects T-cell development and function. T-cell responses are intimately dependent upon survival-promoting signals induced by T-cell receptors (TCRs), the costimulatory molecule CD28, and cytokine receptors. Several transcription factors have been shown to contribute to these processes, including those belonging to NFAT, AP-1, NF-B, and STAT families. 9 We found that viperin Ϫ/Ϫ CD4 ϩ T cells produced a normal amount of IL-2 and were able to respond to polarizing cytokines for T helper 2 (Th2) differentiation. However, there was reduced Th2 cytokine production (IL-4, IL-5, and IL-13) in association with impaired GATA-3 induction in viperin-deficient CD4 ϩ T cells after stimulation with anti-CD3 in the presence or absence of anti-CD28 antibodies. In addition, viperin Ϫ/Ϫ T cells showed decreased DNA binding activities of NF-B1/p50 and JunB in response to TCR ligation in gel-shift assays. These data suggest that viperin induction is required for TCR-mediated NF-B and AP-1 activities, GATA-3 activation, and subsequent Th2 cell development for optimal Th2 response. Methods Generation of viperin-deficient miceMice deficient in viperin was generated using standard procedures. The viperin targeting vector consisted of a 1.8-kb short fragment in putative promoter region, a neomycin resistance gene cassette that replaced exons 1 and 2 as well as an upstream 2.2-kb putative promoter, and a 5.4-kb-long genomic fragment containing exons 3 and 4 (Figure 1 A). One embryonic stem cell clone derived from 129/Sv mice, with a targeted viperin allele detected by Southern blot, was injected into C57BL/6 blastocysts to produce chimeric mice, and germline transmission of the mutation was verified by polymerase chain reaction (PCR) analysis of tail DNA. Reverse transcription (RT)-PCR with primers spanning exons 2 and 3 in enriched...

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Section: Introductionmentioning

confidence: 99%

Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1

Qiu

Cresswell

Chin

2009

Blood

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“…Early studies showed that viperin is induced in various cell types by IFN-α and IFN-β, associates with the cytosolic face of the endoplasmic reticulum (ER), and inhibits human cytomegalovirus replication when preexpressed in human fibroblasts (8). Since then, viperin has been shown to be induced by several factors, including lipopolysaccharide (10)(11)(12), and to inhibit a broad range of viruses, including HIV-1 (13), West Nile virus (14), hepatitis C virus (15,16), dengue virus type 2 (17), influenza A virus (18), and tick-borne encephalitis virus (19). Gene-profiling microarray studies have shown that the viperin gene is one of the most highly inducible ISGs upon infection with a wide range of RNA viruses (20).…”

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Structural studies of viperin, an antiviral radical SAM enzyme

Fenwick

Cresswell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Viperin is an IFN-inducible radical S-adenosylmethionine (SAM) enzyme that inhibits viral replication. We determined crystal structures of an anaerobically prepared fragment of mouse viperin (residues 45-362) complexed with S-adenosylhomocysteine (SAH) or 5′-deoxyadenosine (5′-dAdo) and L-methionine (L-Met). Viperin contains a partial (βα) 6 -barrel fold with a disordered N-terminal extension (residues 45-74) and a partially ordered C-terminal extension (residues 285-362) that bridges the partial barrel to form an overall closed barrel structure. Cys84, Cys88, and Cys91 located after the first β-strand bind a [4Fe-4S] cluster. The active site architecture of viperin with bound SAH (a SAM analog) or 5′-dAdo and L-Met (SAM cleavage products) is consistent with the canonical mechanism of 5′-deoxyadenosyl radical generation. The viperin structure, together with sequence alignments, suggests that vertebrate viperins are highly conserved and that fungi contain a viperin-like ortholog. Many bacteria and archaebacteria also express viperin-like enzymes with conserved active site residues. Structural alignments show that viperin is similar to several other radical SAM enzymes, including the molybdenum cofactor biosynthetic enzyme MoaA and the RNA methyltransferase RlmN, which methylates specific nucleotides in rRNA and tRNA. The viperin putative active site contains several conserved positively charged residues, and a portion of the active site shows structural similarity to the GTPbinding site of MoaA, suggesting that the viperin substrate may be a nucleoside triphosphate of some type.radical SAM | IFN-stimulated gene | antiviral cellular factor | free radical | S-adenosyl methionine V iruses exploit the metabolic machinery of host cells to replicate and spread to other cells. Although cytotoxic T cells and antibody-producing B cells can ultimately be produced in an adaptive response to the virus, innate immune mechanisms are used to respond to infection rapidly. Upon infection, cells can sense the presence of virus via pattern recognition receptors (1, 2) and produce IFNs that limit the spread of infection to other cells (3). IFNs induce the expression of hundreds of IFN-stimulated genes (ISGs), many of which are involved in various antiviral processes, including antigen presentation, apoptosis, and inhibition of viral replication (4-7).Viperin, the product of rsad-2, was first identified as a protein induced by exposure of human macrophages to IFN-γ and by infection of primary human fibroblasts with human cytomegalovirus (8,9). Early studies showed that viperin is induced in various cell types by IFN-α and IFN-β, associates with the cytosolic face of the endoplasmic reticulum (ER), and inhibits human cytomegalovirus replication when preexpressed in human fibroblasts (8). Since then, viperin has been shown to be induced by several factors, including lipopolysaccharide (10-12), and to inhibit a broad range of viruses, including HIV-1 (13), West Nile virus (14), hepatitis C virus (15, 16), dengue virus type 2 (17), influ...

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“…Viperin was then found to be induced by both type I and type II IFN and to exhibit antiviral activity against HCMV (9). Furthermore, the results of several gene-profiling microarray studies showed that the viperin gene is one of those that is highly induced by a range of different viruses (20,25,38,40,42,46) and microbial products, such as lipopolysaccharide (35,42), the double-stranded RNA analog poly(I-C) (39), and double-stranded B-form DNA (22), in various cell types.The human viperin gene encodes a protein of 361 amino acids with a predicted molecular mass of 42.2 kDa. Protein sequence analysis reveals a CX 3 CX 2 C motif, which is found in the superfamily of S-adenosyl methionine (SAM)-dependent radical enzymes (44) in residues 83 to 90 of human viperin.…”

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The Cellular Antiviral Protein Viperin Is Attenuated by Proteasome-Mediated Protein Degradation in Japanese Encephalitis Virus-Infected Cells

Chan

Chang

Liao

et al. 2008

J Virol

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Viperin is identified as an antiviral protein induced by interferon (IFN), viral infections, and pathogenassociated molecules. In this study, we found that viperin is highly induced at the RNA level by Japanese encephalitis virus (JEV) and Sindbis virus (SIN) and that viperin protein is degraded in JEV-infected cells through a proteasome-dependent mechanism. Promoter analysis revealed that SIN induces viperin expression in an IFN-dependent manner but that JEV by itself activates the viperin promoter through IFN regulatory factor-3 and AP-1. The overexpression of viperin significantly decreased the production of SIN, but not of JEV, whereas the proteasome inhibitor MG132 sustained the protein level and antiviral effect of viperin in JEVinfected cells. Knockdown of viperin expression by RNA interference also enhanced the replication of SIN, but not that of JEV. Our results suggest that even though viperin gene expression is highly induced by JEV, it is negatively regulated at the protein level to counteract its antiviral effect. In contrast, SIN induces viperin through the action of IFN, and viperin exhibits potent antiviral activity against SIN.Viperin, an interferon (IFN)-induced cellular antiviral protein, was identified originally as cig5 in human cytomegalovirus (HCMV)-infected human fibroblasts (53). A similar gene called vig-1 was identified subsequently in viral hemorrhagic septicemia virus-infected rainbow trout leukocytes (3) and in mouse dendritic cells infected with vesicular stomatitis virus (VSV) and pseudorabies virus (4). Viperin was then found to be induced by both type I and type II IFN and to exhibit antiviral activity against HCMV (9). Furthermore, the results of several gene-profiling microarray studies showed that the viperin gene is one of those that is highly induced by a range of different viruses (20,25,38,40,42,46) and microbial products, such as lipopolysaccharide (35,42), the double-stranded RNA analog poly(I-C) (39), and double-stranded B-form DNA (22), in various cell types.The human viperin gene encodes a protein of 361 amino acids with a predicted molecular mass of 42.2 kDa. Protein sequence analysis reveals a CX 3 CX 2 C motif, which is found in the superfamily of S-adenosyl methionine (SAM)-dependent radical enzymes (44) in residues 83 to 90 of human viperin. Thus, viperin is also called radical SAM domain-containing 2 (RSAD2). The radical SAM superfamily comprises more than 600 members (44, 47), and evidence suggests that the three conserved cysteine residues are part of an unusual iron-sulfur cluster that uses SAM as a cofactor to form a radical that is involved in catalysis (19,27). Although the precise function of viperin remains to be elucidated, recent data have proven its cellular antiviral effects. The overexpression of viperin reduces productive HCMV infection in human fibroblasts by downregulating several structural proteins that are critical for viral assembly and maturation (9), inhibits influenza virus release by perturbing lipid rafts (48), decreases human hepatitis...

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The Antiviral Cytomegalovirus Inducible Gene 5/Viperin Is Expressed in Atherosclerosis and Regulated by Proinflammatory Agents

Cited by 52 publications

References 18 publications

Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1

Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1

Structural studies of viperin, an antiviral radical SAM enzyme

The Cellular Antiviral Protein Viperin Is Attenuated by Proteasome-Mediated Protein Degradation in Japanese Encephalitis Virus-Infected Cells

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