The Role of Viperin in the Innate Antiviral Response

Helbig, Karla J.; Beard, Michael R.

doi:10.1016/j.jmb.2013.10.019

Cited by 186 publications

(209 citation statements)

References 49 publications

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“…It is a relatively broad antiviral, with demonstrated activity against a variety of DNA and RNA viruses (80,81), such as cytomegalovirus, Chikungunya virus (CHIKV), DENV, hepatitis C virus, Japanese encephalitis virus (JEV), VSV, Sendai virus, WNV, rhinovirus, yellow fever virus (YFV), lymphocytic choriomeningitis virus, Bunyamwera virus, reovirus, and, recently, RSV (82). Unfortunately, in spite of considerable knowledge of the various domains, structure, and cellular location of viperin, the mechanism of how it inhibits such a diverse panel of viruses remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Rabbani

Ribaudo

Guo

et al. 2016

J Virol

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A major arm of cellular innate immunity is type I interferon (IFN), represented by IFN-␣ and IFN-␤. Type I IFN transcriptionally induces a large number of cellular genes, collectively known as IFN-stimulated gene (ISG) proteins, which act as antivirals. The IFIT (interferon-induced proteins with tetratricopeptide repeats) family proteins constitute a major subclass of ISG proteins and are characterized by multiple tetratricopeptide repeats (TPRs). In this study, we have interrogated IFIT proteins for the ability to inhibit the growth of human parainfluenza virus type 3 (PIV3), a nonsegmented negative-strand RNA virus of the Paramyxoviridae family and a major cause of respiratory disease in children. We found that IFIT1 significantly inhibited PIV3, whereas IFIT2, IFIT3, and IFIT5 were less effective or not at all. In further screening a set of ISG proteins we discovered that several other such proteins also inhibited PIV3, including IFITM1, IDO (indoleamine 2,3-dioxygenase), PKR (protein kinase, RNA activated), and viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible)/Cig5. The antiviral effect of IDO, the enzyme that catalyzes the first step of tryptophan degradation, could be counteracted by tryptophan. These results advance our knowledge of diverse ISG proteins functioning as antivirals and may provide novel approaches against PIV3. IMPORTANCE The innate immunity of the host, typified by interferon (IFN), is a major antiviral defense. IFN inhibits virus growth by inducing a large number of IFN-stimulated gene (ISG) proteins, several of which have been shown to have specific antiviral functions.Parainfluenza virus type 3 (PIV3) is major pathogen of children, and no reliable vaccine or specific antiviral against it currently exists. In this article, we report several ISG proteins that strongly inhibit PIV3 growth, the use of which may allow a better antiviral regimen targeting PIV3. P arainfluenza virus type 3 (PIV3) is a nonsegmented, negativestrand RNA virus belonging to the Paramyxoviridae family and a major cause of lower respiratory tract infection in humans and cattle (1-3). Human PIV3 is a particularly serious pathogen in young children, second in clinic importance only to respiratory syncytial virus (RSV), another member of the same family (3). There is currently no specific treatment or approved vaccine for PIV3. However, RNA viruses in general, and paramyxoviruses in particular, induce type I interferon (IFN), a major arm of host innate immunity, mainly by activating a cytoplasmic RNA helicase of the RIG-I family, which is followed by a signaling cascade ultimately leading to transcriptional induction of IFN genes (4-6). Early reports showed that PIV3 is highly sensitive to IFN (7), suggesting that this natural antiviral mechanism holds the potential to be harnessed. Type I IFN by itself has no antiviral activity, but upon binding to its cognate receptor on the cell surface, it triggers the so-called IFN response pathway, in which transcription factors STAT...

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Section: Discussionmentioning

confidence: 99%

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Rabbani

Ribaudo

Guo

et al. 2016

J Virol

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“…: 734-763-6096; E-mail: nmarsh@umich.edu. 3 The abbreviations used are: SAM, S-adenosyl-L-methionine; 5Ј-dA, 5Ј-deoxyadenosine; Ado ⅐ , 5Ј-deoxyadenosyl radical; FPPS, farnesyl pyrophosphate synthase; IPP, isopentenyl pyrophosphate; GPP, geranyl pyrophosphate; NS5A, hepatitis C virus non-structural protein 5A; TBEV, teins, although the specific inhibitory mechanism(s) has yet to be elucidated at the molecular level (20).…”

Section: Radical S-adenosyl-l-methionine-dependent (Sam)mentioning

confidence: 99%

“…It is one of eight putative radical SAM enzymes identified in humans; four of these appear to be involved in tRNA modifications, two seem to be involved in co-factor biosynthesis, and the remaining two, including viperin, have unknown enzymatic activities (23). The human enzyme is a 361-residue protein that comprises three distinct domains: an N-terminal amphipathic helix thought to play a role in localizing viperin to the endoplasmic reticulum and lipid droplets (19); a large, central domain that contains four motifs characteristic of radical SAM enzymes; and a conserved C-terminal domain that may be involved in [Fe 4 S 4 ] cluster assembly, the proper folding of viperin, and/or substrate recognition (20,24). Although no enzymatic function has yet been assigned to viperin, the radical SAM domain has been shown to be important in limiting HIV and Bunyamwera viruses (20).…”

Section: Radical S-adenosyl-l-methionine-dependent (Sam)mentioning

confidence: 99%

“…The human enzyme is a 361-residue protein that comprises three distinct domains: an N-terminal amphipathic helix thought to play a role in localizing viperin to the endoplasmic reticulum and lipid droplets (19); a large, central domain that contains four motifs characteristic of radical SAM enzymes; and a conserved C-terminal domain that may be involved in [Fe 4 S 4 ] cluster assembly, the proper folding of viperin, and/or substrate recognition (20,24). Although no enzymatic function has yet been assigned to viperin, the radical SAM domain has been shown to be important in limiting HIV and Bunyamwera viruses (20). Furthermore, homology modeling suggests that viperin adopts a partial (␤/␣) 6 TIM barrel fold, similar to that of the wellcharacterized radical SAM enzyme, pyruvate formate-lyase activating enzyme (25).…”

Section: Radical S-adenosyl-l-methionine-dependent (Sam)mentioning

confidence: 99%

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Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Makins

Ghosh²,

Román‐Meléndez³

et al. 2016

Journal of Biological Chemistry

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Edited by Charles SamuelViperin is an endoplasmic reticulum-associated antiviral responsive protein that is highly up-regulated in eukaryotic cells upon viral infection through both interferon-dependent and independent pathways. Viperin is predicted to be a radical S-adenosyl-L-methionine (SAM) enzyme, but it is unknown whether viperin actually exploits radical SAM chemistry to exert its antiviral activity. We have investigated the interaction of viperin with its most firmly established cellular target, farnesyl pyrophosphate synthase (FPPS). Numerous enveloped viruses utilize cholesterol-rich lipid rafts to bud from the host cell membrane, and it is thought that by inhibiting FPPS activity (and therefore cholesterol synthesis), viperin retards viral budding from infected cells. We demonstrate that, consistent with this hypothesis, overexpression of viperin in human embryonic kidney cells reduces the intracellular rate of accumulation of FPPS but does not inhibit or inactivate FPPS. The endoplasmic reticulum-localizing, N-terminal amphipathic helix of viperin is specifically required for viperin to reduce cellular FPPS levels. However, although viperin reductively cleaves SAM to form 5-deoxyadenosine in a slow, uncoupled reaction characteristic of radical SAM enzymes, this cleavage reaction is independent of FPPS. Furthermore, mutation of key cysteinyl residues ligating the catalytic [Fe 4 S 4 ] cluster in the radical SAM domain, surprisingly, does not abolish the inhibitory activity of viperin against FPPS; indeed, some mutations potentiate viperin activity. These observations imply that viperin does not act as a radical SAM enzyme in regulating FPPS. Radical S-adenosyl-L-methionine-dependent (SAM)3 enzymes constitute a superfamily of enzymes that use SAM to generate free radicals (1-4). The superfamily is typified by a common CXXXCXXC motif, the cysteinyl residues of which coordinate a [Fe 4 S 4 ] cluster that is essential for radical generation. These enzymes catalyze a remarkably wide range of reactions involving an equally diverse set of substrates (2). For example, radical SAM-dependent enzymes participate in the biosynthesis of herbicides, antibiotics, vitamins, co-factors such as biotin and thiamin, and various other natural products (2, 5-8). They also function in the modification of ribosomal and transfer RNAs (9, 10) and DNA repair (11) and in the post-translational modification of peptides and proteins (12)(13)(14). Sequence analyses indicate that there are potentially thousands of members of the radical SAM superfamily, but to date, relatively few of these enzymes have been isolated and characterized (15, 16). Radical SAM enzymes were until recently thought to be confined to the microbial realm but intriguingly have now been identified in higher aerobic organisms, including plants and animals (3).Central to the mechanism of all radical SAM enzymes is the generation of a highly reactive 5Ј-deoxyadenosyl radical (Ado ⅐ ) (1,4,17). This is accomplished through one-electron reduction of SAM by the [Fe 4...

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“…IFIT genes have previously been shown to be induced by pneumococci in a pneumolysin-independent manner (23). Other interferon-induced genes found in the pattern B group included the antiviral protein viperin, encoded by the RSAD2 gene (24), and the chemokine CXCL10 gene (25). Interferon-related genes are known for their antiviral properties, but more recent findings suggest that they also play a central role in bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

Intact Pneumococci Trigger Transcription of Interferon-Related Genes in Human Monocytes, while Fragmented, Autolyzed Bacteria Subvert This Response

et al. 2017

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A peculiar trait of pneumococci (Streptococcus pneumoniae) is their propensity to undergo spontaneous lysis during stationary growth due to activation of the enzyme autolysin (LytA), which fragments the peptidoglycan cell wall. The fragments that are generated upon autolysis impair phagocytosis and reduce production of interleukin-12 (IL-12) and gamma interferon (IFN-␥) by human leukocytes in response to intact pneumococci, thereby impeding crucial host defenses. The objective was to identify additional monocyte genes whose transcription is induced by intact pneumococci and subverted by autolyzed bacteria. Monocytes were isolated from healthy blood donors and stimulated for 3 h with UV-inactivated S. pneumoniae (Rx1PLY Ϫ LytA ϩ strain), which is capable of autolyzing, its LytA Ϫ isogenic autolysindeficient mutant, or a mixture of the two (containing twice the initial bacterial concentration). Gene expression was assessed by Illumina microarray, and selected findings were confirmed by reverse transcription-quantitative real-time PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. In all, we identified 121 genes that were upregulated to a significantly higher degree by intact than autolyzed pneumococci. These included IFNB1 and a large set of interferon-induced genes, such as IFIT3, RSAD2, CFCL1, and CXCL10 genes, as well as IL12B and CD40 genes. RT-qPCR revealed that transcription of these genes in response to intact pneumococci diminished when autolyzed pneumococci were admixed and that this pattern was independent of pneumolysin. Thus, transcription of interferon-related genes is triggered by intact pneumococci and subverted by fragments generated by spontaneous bacterial autolysis. We suggest that interferon-related pathways are important for elimination of pneumococci and that autolysis contributes to virulence by extinguishing these pathways. KEYWORDS Streptococcus pneumoniae, autolysins, inflammation, interferons Infection by the pneumococcus (Streptococcus pneumoniae) is a leading cause of death in young children worldwide (1). Pneumococci are one of the major causes of pneumonia, sepsis, and meningitis, as well as less severe localized respiratory infections, such as acute otitis media and sinusitis.The major defense against pneumococcal infection is phagocyte-mediated killing, and the most prominent virulence factor is the thick and hydrophilic pneumococcal capsule, which impedes phagocytosis. Another well-recognized virulence factor is pneumolysin, a cytolysin that incorporates into cholesterol-rich eukaryotic cell membranes. When present in high concentrations, it lyses the host cells (2), while lower

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The Role of Viperin in the Innate Antiviral Response

Cited by 186 publications

References 49 publications

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Intact Pneumococci Trigger Transcription of Interferon-Related Genes in Human Monocytes, while Fragmented, Autolyzed Bacteria Subvert This Response

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