Affinage

RSAD2

S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 · UniProt Q8WXG1

Length
361 aa
Mass
42.2 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Viperin (RSAD2) is an interferon-inducible radical SAM enzyme that couples a metabolic catalytic activity to broad antiviral and immunomodulatory functions (PMID:20176015, PMID:32603630). It binds a [4Fe-4S] cluster coordinated by Cys84/Cys88/Cys91 in its N-terminal radical SAM domain, generating a 5'-deoxyadenosyl radical from SAM, and its mature cluster is installed by a minimal CIA pathway in which CIAO1 is the predominant Fe-S insertion factor binding the C-terminal residue W361 (PMID:20176015, PMID:24245804, PMID:28615450). Crystal structures define a partial (βα)6-barrel closed by a C-terminal extension and a nucleotide-binding active site that selects CTP over UTP (PMID:28607080, PMID:31917549). Catalytically, viperin converts CTP to the chain-terminating nucleotide ddhCTP, which causes premature termination of viral RNA-dependent RNA polymerases and also triggers ribosome collisions that activate a ZAK→GCN2 integrated-stress-response axis to suppress translation (PMID:32603630, PMID:31917549, PMID:35316659). Viperin localizes constitutively to the cytosolic face of the ER and to lipid droplets via an N-terminal amphipathic α-helix that is necessary and sufficient for this targeting and for inhibiting ER-to-Golgi secretory trafficking (PMID:11752458, PMID:19074433, PMID:19920176). From these membranes it restricts diverse viruses through multiple mechanisms: inhibiting farnesyl diphosphate synthase to disrupt lipid rafts at viral budding sites (PMID:18005724), directing flavivirus NS3 and HCV NS5A to proteasomal degradation (PMID:29321318, PMID:31977203), interfering with host trafficking factors GBF1 and VAP-A required for replication-complex assembly (PMID:22045669, PMID:29046456), and during HCMV infection relocalizing to mitochondria via the viral protein vMIA to inhibit the trifunctional enzyme HADHB, lowering ATP and remodeling the actin cytoskeleton and lipogenic metabolism through AMPK/ChREBP signaling (PMID:21527675, PMID:23935494, PMID:31980458). Beyond direct restriction, viperin amplifies innate immunity by binding IRAK1 and TRAF6 to drive K63-linked IRAK1 ubiquitination and IRF7-dependent type I IFN in plasmacytoid dendritic cells, and by binding STING to enhance TBK1 ubiquitination, while reciprocally IRAK1/TRAF6 and HADHB stimulate its catalytic output ~10-fold (PMID:21435586, PMID:30872404, PMID:31980458, PMID:33131099). Viperin protein abundance is controlled by HAT1-mediated Lys197 acetylation that recruits UBE4A for K6-linked polyubiquitination and proteasomal degradation, and its mRNA is cleaved by RNase MRP/RNase P (PMID:31812350, PMID:21053045). Independent of infection, viperin shapes adipose thermogenesis and fatty-acid β-oxidation in a Fe-S-cluster-dependent manner (PMID:31341090).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established that viperin is an ER-localized antiviral effector, setting the foundational localization and restriction phenotype before any enzymatic role was known.

    Evidence Stable expression with immunofluorescence, fractionation, and HCMV titer/structural-protein assays

    PMID:11752458

    Open questions at the time
    • Molecular mechanism of HCMV protein downregulation not defined
    • No enzymatic activity attributed yet
  2. 2007 High

    Identified the first molecular target, FPPS, linking viperin to lipid-raft disruption as a mechanism of antiviral restriction.

    Evidence Co-IP, FPPS activity assay, reciprocal siRNA/overexpression, lipid-raft fractionation in influenza model

    PMID:18005724

    Open questions at the time
    • Whether FPPS inhibition is enzymatic or stoichiometric unresolved
    • Generality across viruses untested at this stage
  3. 2008 High

    Mapped the N-terminal amphipathic helix as the necessary and sufficient ER/lipid-droplet targeting determinant and showed it impairs secretory trafficking, defining how viperin reaches its membrane sites of action.

    Evidence Site-directed mutagenesis, reporter trafficking assays, EM, co-IP self-association

    PMID:19074433 PMID:19920176

    Open questions at the time
    • Functional consequence of crystalloid ER for antiviral activity unclear
    • Self-association role not mechanistically defined
  4. 2010 High

    Demonstrated biochemically that viperin is a radical SAM enzyme with a [4Fe-4S] cluster, transforming it from an effector of unknown chemistry into a defined catalytic enzyme.

    Evidence In vitro Fe-S reconstitution, EPR, and HPLC/MS detection of 5'-deoxyadenosine; soluble-fragment reconstitution

    PMID:20026307 PMID:20176015

    Open questions at the time
    • Physiological substrate unknown at this point
    • Link between catalysis and antiviral function not established
  5. 2011 High

    Showed viperin amplifies TLR7/9-driven type I IFN by recruiting IRAK1 and TRAF6 to lipid bodies and promoting K63-ubiquitination of IRAK1, establishing a signaling-scaffold role distinct from direct restriction.

    Evidence Co-IP, ubiquitination assays, viperin-KO mice, IRF7 translocation, IFN ELISA

    PMID:21435586

    Open questions at the time
    • Whether catalysis contributes to the scaffolding function not addressed here
    • Cell-type specificity to pDCs not generalized
  6. 2011 High

    Defined the HCMV-specific mitochondrial relocalization (via vMIA) and HADHB inhibition that lowers ATP and disrupts actin, revealing a proviral, metabolism-targeting arm of viperin biology.

    Evidence Co-IP, mitochondrial fractionation, ATP/actin readouts, Fe-S mutant controls in HCMV model

    PMID:21527675

    Open questions at the time
    • Mechanism by which Fe-S motif mediates HADHB binding unclear
    • Why a host antiviral protein is co-opted to aid HCMV not fully resolved
  7. 2011 High

    Extended viperin restriction to HCV by showing interaction with NS5A and the host trafficking factor VAP-A/hVAP-33 at the replication complex, with C-terminal determinants required for partner binding.

    Evidence FRET, co-IP, competitive co-IP, mutagenesis, HCV replication assays

    PMID:21957124 PMID:22045669

    Open questions at the time
    • Stoichiometry of ternary complex disruption not quantified
    • Catalytic contribution untested in this work
  8. 2013 High

    Connected the mitochondrial HADHB inhibition to a downstream AMPK/ChREBP lipogenic program, and established CIAO1-dependent Fe-S maturation as required for antiviral activity against flaviviruses.

    Evidence Mitochondrial targeting constructs, AMPK/glucose/ChREBP/lipidomic readouts; 55Fe labeling, cysteine mutagenesis, CIAO1 co-IP, SAM depletion

    PMID:23935494 PMID:24245804

    Open questions at the time
    • Substrate of the radical SAM reaction still unidentified at this stage
    • How ER localization couples to catalysis unclear
  9. 2017 High

    Solved crystal structures revealing a closed (βα)6-barrel with positively charged active site resembling a nucleotide-binding pocket, predicting a nucleoside triphosphate substrate before its identification.

    Evidence Anaerobic X-ray crystallography of mouse viperin with SAH or 5'-dAdo/L-Met

    PMID:28607080

    Open questions at the time
    • Actual substrate not bound in these structures
    • Catalytic product not yet defined
  10. 2017 High

    Defined the minimal CIA maturation pathway (CIAO1 predominant; CIA2A/CIA2B/MMS19 differential binding) and identified additional host targets (GBF1) and a catalysis-independent route to FPPS downregulation.

    Evidence 55Fe labeling with CIA-factor RNAi and co-IP; GBF1 interactome/co-IP/rescue; FPPS co-expression with Fe-S mutants

    PMID:27834682 PMID:28615450 PMID:29046456

    Open questions at the time
    • How distinct CIA factors are selected for viperin unclear
    • Mechanistic basis of catalysis-independent FPPS reduction undefined
  11. 2019 High

    Established reciprocal regulation between catalysis and signaling: IRAK1/TRAF6 boost ddhCTP synthesis ~10-fold while catalytically inactive viperin still supports IRAK1 ubiquitination, and defined PTM-driven viperin turnover via HAT1/UBE4A.

    Evidence In-cell ddhCTP LC-MS, co-IP, ubiquitination with SAM/catalytic mutants; MS-mapped acetylation, UBE4A-KO, in vivo interfering peptides

    PMID:30872404 PMID:31812350

    Open questions at the time
    • Whether SAM-induced conformational change is required in vivo not fully resolved
    • Tissue scope of HAT1/UBE4A regulation limited to epithelial cells
  12. 2019 High

    Revealed infection-independent metabolic roles: viperin regulates adipose thermogenesis and fatty-acid β-oxidation in a Fe-S-dependent, adipocyte-autonomous manner, and modulates Th2 cytokine programs.

    Evidence Viperin-KO mice, calorimetry, high-fat-diet phenotyping, Fe-S mutant rescue; KO T-cell cytokine and EMSA assays

    PMID:19047684 PMID:31341090

    Open questions at the time
    • Molecular substrate underlying thermogenic regulation undefined
    • Mechanism linking viperin to NF-kB/AP-1 DNA binding unclear
  13. 2020 High

    Identified ddhCTP as the catalytic product and chain terminator of viral RdRps, finally linking viperin's enzymology to its antiviral mechanism, with structures explaining CTP-over-UTP selectivity.

    Evidence In vitro radical SAM assays, LC-MS of ddhCTP, RdRp chain-termination and cell antiviral assays; CTP/UTP-bound structures with kinetics

    PMID:31917549 PMID:32603630

    Open questions at the time
    • Spectrum of viral polymerases sensitive to ddhCTP not exhaustively defined
    • In vivo ddhCTP concentrations and turnover not quantified
  14. 2020 Medium

    Showed ddhCTP and viperin act on host metabolism and signaling beyond chain termination, including GAPDH inhibition, HADHB thiolase inhibition with reciprocal activation, STING/TBK1 amplification, and MAVS-based self-limitation.

    Evidence Metabolomics and enzyme-inhibition/docking; purified-enzyme HADHB assays; STING and MAVS co-IP with IFN reporters and CIA2A/SAM mutants

    PMID:28207838 PMID:31980458 PMID:32232843 PMID:33131099

    Open questions at the time
    • Physiological significance of GAPDH inhibition not established in vivo
    • How catalysis self-limits immunomodulation mechanistically unclear
  15. 2022 High

    Connected ddhCTP to a ribosome-collision-driven ZAK→GCN2 stress pathway, expanding viperin's antiviral output to broad translational shutdown.

    Evidence Ribosome profiling, ZAK/GCN2 KOs, SAM-mutant viperin, direct ddhCTP addition

    PMID:35316659

    Open questions at the time
    • Selectivity of translation inhibition for viral vs host mRNAs incompletely defined
    • Quantitative contribution relative to RdRp chain termination unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How viperin's single catalytic activity is partitioned and prioritized among its many membrane-localized restriction, signaling-scaffold, and host-metabolic roles in physiological infection remains unresolved.
  • No unifying model reconciles catalysis-dependent vs catalysis-independent functions in vivo
  • Relative contribution of each mechanism to organismal antiviral immunity not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005783 endoplasmic reticulum 3 GO:0005811 lipid droplet 3 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
CIAO1FPPSGBF1HADHBIRAK1MAVSSTINGTRAF6

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Viperin localizes to the cytoplasmic face of the endoplasmic reticulum under normal conditions; HCMV infection causes redistribution first to the Golgi apparatus and then to cytoplasmic vacuoles containing viral proteins gB and pp28, and stable viperin expression before infection inhibits productive HCMV replication by downregulating viral structural proteins (gB, pp28, pp65). Stable cell line expression, immunofluorescence microscopy, subcellular fractionation, viral titer assays Proceedings of the National Academy of Sciences of the United States of America High 11752458
2007 Viperin inhibits influenza A virus release from the plasma membrane by interacting intracellularly with farnesyl diphosphate synthase (FPPS), decreasing its enzymatic activity, which reduces isoprenoid biosynthesis and alters lipid raft formation at sites of viral budding. Overexpression of FPPS reversed viperin-mediated inhibition, and siRNA knockdown of FPPS phenocopied viperin overexpression. Co-immunoprecipitation, FPPS activity assays, siRNA knockdown, lipid raft fractionation, viral titer assays Cell host & microbe High 18005724
2008 The N-terminal amphipathic alpha-helix of viperin is necessary and sufficient for localization to the cytosolic face of the ER, and intact viperin (but not the isolated helix) induces crystalloid ER formation. Viperin self-associates independently of the amphipathic helix. Viperin expression inhibits secretion of soluble proteins (alkaline phosphatase, alpha-1-antitrypsin, serum albumin) by retarding ER-to-Golgi trafficking; hydrophobic-to-acidic mutations in the helix partially or completely restore secretion. Site-directed mutagenesis, reporter protein trafficking assays, immunofluorescence, co-immunoprecipitation for self-association, electron microscopy of crystalloid ER The Journal of biological chemistry High 19074433
2009 The N-terminal amphipathic alpha-helix of viperin is necessary and sufficient to localize viperin to lipid droplets as well as the ER. Point mutations in the helix that prevent ER association also disrupt lipid droplet association. The amphipathic helix of HCV NS5A can similarly direct viperin to lipid droplets, suggesting a shared targeting mechanism. Deletion and point mutant constructs, fluorescence microscopy with dsRed fusion reporter, co-localization with lipid droplet markers Proceedings of the National Academy of Sciences of the United States of America High 19920176
2010 Viperin binds an iron-sulfur [4Fe-4S] cluster; addition of S-adenosylmethionine (SAM) alters the EPR g-values consistent with SAM coordination to the cluster, and incubation of reduced viperin with SAM results in reductive cleavage to produce 5'-deoxyadenosine, establishing viperin as a radical SAM enzyme. Iron analysis, UV-Vis spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, HPLC and mass spectrometry identification of 5'-deoxyadenosine FEBS letters High 20176015
2009 Reconstitution of the [4Fe-4S] cluster in the soluble viperin fragment (residues 45–361) confirmed viperin as a radical SAM enzyme; the C-terminal domain is only partially folded in isolation. CD spectroscopy, NMR spectroscopy, in vitro [4Fe-4S] cluster reconstitution Biochemical and biophysical research communications Medium 20026307
2011 HCMV-induced viperin is relocalized from the ER to mitochondria via interaction with the viral protein vMIA. At mitochondria, viperin interacts with the mitochondrial trifunctional protein (TFP/HADHB) that mediates fatty acid β-oxidation, reducing cellular ATP generation; this disrupts the actin cytoskeleton and enhances HCMV infection. The Fe-S cluster-binding motif of viperin is required for this interaction. Co-immunoprecipitation, mitochondrial fractionation, ATP measurement, actin cytoskeleton imaging, viperin iron-sulfur cluster mutant analysis, viral infectivity assays Science (New York, N.Y.) High 21527675
2011 Viperin promotes TLR7- and TLR9-mediated type I interferon production in plasmacytoid dendritic cells (pDCs) by localizing to lipid bodies and interacting with IRAK1 and TRAF6, recruiting them to lipid bodies and facilitating K63-linked ubiquitination of IRAK1, which drives IRF7 nuclear translocation. Viperin knockout mice have reduced TLR7/9-dependent IFN production but normal responses to intracellular nucleic acids. Co-immunoprecipitation, ubiquitination assays, viperin-knockout mice, IRF7 nuclear translocation assays, IFN ELISA, confocal microscopy Immunity High 21435586
2011 Viperin inhibits HCV replication by co-localizing and interacting with NS5A at the lipid-droplet interface and also associating with the host factor VAP-A at the HCV replication complex. The N-terminal amphipathic helix is required for LD/ER localization and antiviral activity; C-terminal mutants localize correctly but lose NS5A interaction and antiviral function. Confocal microscopy, FRET analysis, co-immunoprecipitation, deletion/point mutant analysis, viral RNA/titer assays Hepatology (Baltimore, Md.) High 22045669
2011 Viperin competitively interacts with host protein hVAP-33 via its C-terminus, interfering with the hVAP-33–NS5A interaction required for HCV replication complex assembly. Co-immunoprecipitation, competitive co-IP, confocal microscopy, dose-dependent HCV replication assays, C-terminal mutagenesis The Journal of general virology Medium 21957124
2012 HIV-1 infection induces viperin redistribution to CD81 compartments (the site of HIV-1 egress) and viperin disrupts lipid rafts to inhibit HIV-1 production in macrophages. The internal SAM domains of viperin are essential for its antiviral activity against HIV-1; exogenous farnesol (enhancing protein prenylation) reverses the inhibition. Immunofluorescence, flow cytometry, mutagenesis of SAM domain, farnesol rescue experiment, viral titer assays Blood Medium 22677126
2013 HCMV-induced viperin redistribution to mitochondria and its interaction with/inhibition of TFP causes decreased cellular ATP, activating AMPK, which induces GLUT4 expression and increased glucose import. This drives ChREBP nuclear translocation, upregulation of lipogenic enzymes, lipid droplet accumulation, and HCMV envelope generation. The Fe-S cluster-binding motif is essential; all these outcomes can be replicated by directly targeting viperin to mitochondria without HCMV. Mitochondrial targeting constructs, AMPK activity assays, glucose uptake assays, ChREBP nuclear translocation assay, lipidomics, Fe-S cluster mutant controls, viral titer assays PLoS pathogens High 23935494
2013 Viperin requires an intact [4Fe-4S] cluster (coordinated by Cys84, Cys88, Cys91 in the radical SAM domain) and SAM for antiviral activity against tick-borne encephalitis virus (TBEV) genome RNA synthesis. Viperin maturation requires the cytosolic iron-sulfur protein assembly factor CIAO1 for Fe-S cluster insertion; the C-terminal residue W361 is required for CIAO1 interaction. ER localization is required for full antiviral activity. 55Fe radiolabeling, cysteine mutagenesis, CIAO1 interaction (co-IP), ectopic SAMase expression to deplete SAM, antiviral activity assays Cellular microbiology High 24245804
2017 Crystal structures of mouse viperin (residues 45–362) with SAH or 5'-dAdo/L-Met reveal a partial (βα)6-barrel fold; Cys84, Cys88, Cys91 coordinate a [4Fe-4S] cluster; active site architecture is consistent with canonical 5'-deoxyadenosyl radical generation. The C-terminal extension bridges the partial barrel to form a closed barrel. The active site contains conserved positively charged residues and structural similarity to the GTP-binding site of MoaA, suggesting a nucleoside triphosphate substrate. X-ray crystallography (anaerobically prepared protein), sequence alignments, structural alignments Proceedings of the National Academy of Sciences of the United States of America High 28607080
2017 Viperin interacts with and inhibits GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1), leading to release of noninfectious, malfunctioning TBEV capsid particles. GBF1 knockdown or inhibition stimulates viperin antiviral activity and capsid particle release; GBF1 overexpression reverses the viperin effect. Viperin interactome analysis (proteomics), co-immunoprecipitation, GBF1 siRNA knockdown and overexpression, electron microscopy of particle release, viral titer assays Journal of virology High 29046456
2017 Cellular requirements for Fe-S cluster insertion into viperin: CIA1 (CIAO1) is the predominant factor required for 55Fe incorporation, while CIA2B and MMS19 interact with the C-terminus of viperin via CIA1, and CIA2A binds the N-terminus independently of CIA1/CIA2B/MMS19. This represents a novel, minimal CIA pathway for viperin maturation. Co-immunoprecipitation, 55Fe radiolabeling in human cells depleted of CIA factors by RNAi, deletion mutant analysis The Journal of biological chemistry High 28615450
2018 Viperin targets flavivirus NS3 protein for proteasome-dependent degradation, reducing levels of NS3 and NS3-dependent viral proteins. Viperin interacts with TBEV structural proteins prM and E and nonstructural proteins NS2A, NS2B, and NS3, but only ZIKV and TBEV NS3 are sensitive to viperin-induced proteasomal degradation. Overexpression of NS3 fully rescues viral replication. Co-immunoprecipitation, proteasome inhibitor rescue experiments, NS3 overexpression rescue, viral titer and RNA assays Journal of virology High 29321318
2019 Viperin is acetylated at Lys197 by the acetyltransferase HAT1 in response to virus/IFN stimulation in epithelial cells. This acetylation recruits UBE4A, which catalyzes K6-linked polyubiquitination at Lys206 of viperin, leading to its proteasomal degradation. UBE4A deficiency restores viperin protein production; interfering peptides blocking UBE4A-viperin interaction enhance antiviral activity in vivo. Mass spectrometry identification of acetylation site, co-immunoprecipitation, ubiquitination assays, UBE4A KO cells, mouse viral challenge model with interfering peptides Molecular cell High 31812350
2019 Viperin interacts with IRAK1 and TRAF6 together; IRAK1 and TRAF6 increase viperin's CTP→ddhCTP enzymatic activity ~10-fold in reconstituted HEK293T cells. Conversely, viperin association with both IRAK1 and TRAF6 is required for TRAF6-mediated K63 ubiquitination of IRAK1. SAM binding induces structural changes in viperin required for ubiquitination, but catalytically inactive viperin still supports ubiquitination. Transient co-expression in HEK293T, in-cell ddhCTP activity assay (LC-MS), co-immunoprecipitation, ubiquitination assays with SAM-binding and catalytic mutants The Journal of biological chemistry High 30872404
2020 Viperin catalyzes the radical SAM-dependent conversion of CTP to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP). Incorporation of ddhCTP causes premature termination of RNA synthesis by viral RNA-dependent RNA polymerases, representing the direct link between viperin's enzymatic activity and antiviral function in human cells. In vitro radical SAM enzyme assay, LC-MS identification of ddhCTP, RNA polymerase chain-termination assays, cell-based antiviral assays Annual review of virology High 32603630
2020 Crystal structures of viperin bound to SAM analogue with CTP or UTP define the active site for substrate selectivity: CTP4' H is positioned for radical abstraction; UTP binds more weakly (higher Km, similar kcat) due to unfavorable interactions of the uracil moiety. Nucleotide binding orders the C-terminal tail, which contains a P-loop that coordinates the γ-phosphate. X-ray crystallography (CTP- and UTP-bound structures), enzyme kinetics (kcat, Km determination) Biochemistry High 31917549
2020 Targeting viperin to mitochondria inhibits the thiolase activity of the mitochondrial trifunctional enzyme (HADHB subunit) using purified enzymes. Reciprocally, HADHB activates viperin ~10-fold for ddhCTP synthesis. Viperin co-localization with HADHB also increases HADHB retrotranslocation and degradation from mitochondria. Mitochondrially targeted viperin decreases cellular ATP by >50%. In vitro enzyme assays with purified proteins, cell lysate activity assays, mitochondrial targeting constructs, cellular ATP measurement The Journal of biological chemistry High 31980458
2020 Viperin co-localizes with and directly binds STING, and enhances K63-linked polyubiquitination of TBK1, amplifying the dsDNA-sensing innate immune signaling pathway. This function requires viperin's interaction with CIA2A; viperin's radical SAM enzymatic activity self-limits its immunomodulatory function. Co-immunoprecipitation, confocal co-localization, ubiquitination assays, CIA2A interaction assays, IFN reporter assays, SAM mutant analysis Immunology and cell biology Medium 33131099
2020 ddhCTP produced by viperin's radical SAM activity inhibits the NAD+-dependent activity of enzymes including GAPDH, as determined by biochemical assays and molecular docking in macrophages; this points to viperin modulating cellular metabolism beyond chain termination. LC-MS/MS metabolite analysis in hiPSC-derived macrophages, biochemical enzyme inhibition assays, molecular docking simulations FEBS letters Medium 32232843
2021 Viperin activates TRAF6 E3 ubiquitin ligase activity, stimulating K63-linked ubiquitin transfer by ~2.5-fold and increasing TRAF6 polyubiquitinated forms; this requires direct viperin-TRAF6 binding. Co-immunoprecipitation, in vitro and in-cell ubiquitination assays, immunoblotting Journal of the American Chemical Society Medium 33779167
2022 Viperin activates a ribosome collision-dependent translation inhibition pathway via its radical SAM-dependent production of ddhCTP. ddhCTP triggers ribosome collisions that activate the MAPKKK ZAK pathway, which in turn activates the GCN2 arm of the integrated stress response to inhibit both cellular and viral RNA translation. Ribosome profiling, translation inhibition assays, ZAK and GCN2 genetic knockouts, SAM mutant viperin, ddhCTP addition experiments Molecular cell High 35316659
2008 Viperin is required for optimal Th2 cytokine production (IL-4, IL-5, IL-13) and GATA3 activation in CD4+ T cells following TCR engagement, correlating with decreased NF-κB1/p50 and AP-1/JunB DNA-binding activity in viperin-deficient T cells. Viperin-knockout mice, T cell cytokine assays (ELISA), EMSA for NF-κB and AP-1 DNA binding, Th2 differentiation assays Blood Medium 19047684
2010 Viperin mRNA is a direct substrate for cleavage by RNase MRP/RNase P endoribonucleases in human cells; two cleavage sites were identified in the viperin coding sequence, and upregulation of viperin mRNA upon RNase MRP depletion is independent of the interferon response. DNA microarray, RNAi depletion of RNase MRP, in vitro cleavage assays, cleavage site mapping Cellular and molecular life sciences : CMLS Medium 21053045
2017 Viperin interacts with IRAK1 and TRAF6 and the interaction with HSV-1 glycoprotein D (gD) promotes viperin-IRAK1 interaction and K63-linked IRAK1 polyubiquitination, increasing IRF7-mediated IFN-β expression; simultaneously, gD inhibits TRAF6-induced NF-κB activity by decreasing viperin-TRAF6 interaction. Co-immunoprecipitation, dual-luciferase reporter assays, confocal microscopy, co-transfection of interaction domain mutants Frontiers in immunology Medium 31921110
2017 Viperin expression reduces cellular FPPS protein levels in HEK cells via its N-terminal amphipathic helix (not via radical SAM activity). Viperin performs slow uncoupled SAM reductive cleavage but Fe-S cluster mutations that abolish catalytic activity do not abolish FPPS inhibition—some even potentiate it—indicating viperin does not act as a radical SAM enzyme in regulating FPPS levels. Viperin/FPPS co-expression, FPPS activity assays, Fe-S cluster cysteine mutants, cellular cholesterol/FPPS level measurement The Journal of biological chemistry Medium 27834682
2017 Viperin interacts with MAVS (mitochondrial antiviral signaling protein), most likely at mitochondria-associated membranes, and this interaction limits viperin's ability to negatively regulate the interferon response in macrophages. Co-immunoprecipitation, subcellular fractionation, viperin overexpression/KO in macrophages, IFN reporter assays PloS one Medium 28207838
2019 Viperin interacts with the mitochondrial trifunctional enzyme β-subunit (HADHB) and with rotavirus NSP4; NSP4 triggers viperin relocalization from the ER to mitochondria and viperin inhibits NSP4 mitochondrial translocation, reducing cytochrome c release and intrinsic apoptosis. This delays rotavirus release. The interaction requires both the radical SAM and C-terminal domains of viperin. Co-immunoprecipitation, immunofluorescence, cytochrome c release assay, apoptosis assay, viperin knockdown, domain deletion analysis Viruses Medium 34372530
2019 In adipose tissues, intrinsic (non-infection-induced) viperin expression regulates thermogenesis: viperin KO mice show increased heat production, reduced fat mass, improved glucose tolerance on high-fat diet, and enhanced cold tolerance via an adipocyte-autonomous mechanism that regulates fatty acid β-oxidation. The Fe-S cluster-binding motif is essential for this function. Viperin-knockout mice, indirect calorimetry, metabolic phenotyping, high-fat diet model, Fe-S cluster mutant analysis, adipocyte-specific rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 31341090
2021 Viperin expression reduces cellular cholesterol by 20–30% in HEK293T cells. Proteomics identified lanosterol synthase (LS) and squalene monooxygenase (SM) as viperin interactors; co-IP confirmed formation of a viperin-LS-SM complex at the ER membrane. Viperin significantly inhibits LS specific activity; viperin coexpression reduces SM protein levels ~30% without affecting its activity. Proteomics interactome screen, co-immunoprecipitation, cholesterol measurement, LS and SM enzymatic activity assays, immunoblotting The Journal of biological chemistry Medium 34029588
2020 Viperin interacts with HCV NS5A and VAP-33C independently; the viperin-NS5A-VAP-33C ternary complex at the ER membrane exhibits the lowest viperin-specific ddhCTP synthetic activity, suggesting NS5A inhibits viperin enzymatic activity. Viperin coexpression with NS5A reduces cellular NS5A levels via proteasomal degradation, even when viperin is catalytically inactive (Fe-S cluster mutant). Transfected HEK293T cells, co-immunoprecipitation, in-cell ddhCTP activity measurement, proteasome inhibitor experiments, Fe-S cluster mutant Biochemistry Medium 31977203
2019 Viperin regulates chondrogenic differentiation by influencing TGF-β/SMAD2/3 signaling via secretion of CXCL10; viperin knockdown or overexpression modulates CXCL10 secretion and downstream SMAD2/3 activity in chondrocytic cells. This axis is disturbed in cartilage-hair hypoplasia (CHH) chondrocytic cells. siRNA knockdown, plasmid overexpression, ELISA for CXCL10, SMAD2/3 phosphorylation assays, label-free MS proteomics, promoter reporter assays The Journal of biological chemistry Medium 30718282
2018 Viperin inhibits enterovirus A71 (EVA71) by interacting with the viral 2C protein at the ER; the N-terminal domain of viperin (amino acids 50–60) is required for both 2C interaction and antiviral activity. Co-immunoprecipitation, immunofluorescence confocal microscopy, N-terminal deletion/point mutant analysis, viral titer assays Viruses Medium 30587778
2006 In human astrocytes, viperin/cig5 induction by TLR3 ligation is dependent on IRF3 and NF-κB signaling, and is substantially inhibited by anti-IFN-β neutralizing antibodies. RNAi knockdown of viperin significantly reverses pIC-induced inhibition of HIV-1 replication in astrocytes. siRNA knockdown, RNAi, neutralizing antibody, IRF3/NF-κB signaling pathway analysis, HIV-1 pseudovirus replication assay Journal of immunology (Baltimore, Md. : 1950) Medium 16982913
2018 Rsad2 is required for dendritic cell maturation via the IRF7-mediated signaling pathway; Rsad2 knockdown in bone marrow-derived DCs markedly attenuates DC maturation and antitumor efficacy in a lung metastasis model. siRNA knockdown, flow cytometry, ELISA, western blotting, confocal microscopy, in vivo tumor model Cell death & disease Medium 30068989

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell host & microbe 380 18005724
2001 Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proceedings of the National Academy of Sciences of the United States of America 354 11752458
2011 Viperin: a multifunctional, interferon-inducible protein that regulates virus replication. Cell host & microbe 205 22177558
2005 Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector. Hepatology (Baltimore, Md.) 198 16108059
2009 The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic alpha-helix. Proceedings of the National Academy of Sciences of the United States of America 196 19920176
2012 HIV-1 infection of human macrophages directly induces viperin which inhibits viral production. Blood 195 22677126
2011 Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity 182 21435586
2013 The role of viperin in the innate antiviral response. Journal of molecular biology 173 24157441
2011 Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. Science (New York, N.Y.) 171 21527675
2011 The antiviral protein viperin inhibits hepatitis C virus replication via interaction with nonstructural protein 5A. Hepatology (Baltimore, Md.) 171 22045669
2012 Viperin restricts chikungunya virus replication and pathology. The Journal of clinical investigation 162 23160199
2013 Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin. PLoS neglected tropical diseases 138 23638199
2010 The interferon inducible gene: Viperin. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 134 21142818
2008 The N-terminal amphipathic alpha-helix of viperin mediates localization to the cytosolic face of the endoplasmic reticulum and inhibits protein secretion. The Journal of biological chemistry 127 19074433
2006 TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5. Journal of immunology (Baltimore, Md. : 1950) 122 16982913
2011 The interferon-inducible gene viperin restricts West Nile virus pathogenesis. Journal of virology 118 21880757
2018 Viperin Restricts Zika Virus and Tick-Borne Encephalitis Virus Replication by Targeting NS3 for Proteasomal Degradation. Journal of virology 103 29321318
2020 Viperin Reveals Its True Function. Annual review of virology 100 32603630
2013 Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. PLoS pathogens 97 23935494
2011 Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33. The Journal of general virology 95 21957124
2010 The antiviral protein viperin is a radical SAM enzyme. FEBS letters 95 20176015
2017 Viperin is an important host restriction factor in control of Zika virus infection. Scientific reports 91 28667332
2013 Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity. Cellular microbiology 87 24245804
2011 Viperin, a key player in the antiviral response. Microbes and infection 84 22182524
2008 The cellular antiviral protein viperin is attenuated by proteasome-mediated protein degradation in Japanese encephalitis virus-infected cells. Journal of virology 77 18768981
2008 Viperin is required for optimal Th2 responses and T-cell receptor-mediated activation of NF-kappaB and AP-1. Blood 70 19047684
2017 Structural studies of viperin, an antiviral radical SAM enzyme. Proceedings of the National Academy of Sciences of the United States of America 69 28607080
2009 Structural characterization reveals that viperin is a radical S-adenosyl-L-methionine (SAM) enzyme. Biochemical and biophysical research communications 67 20026307
2007 Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus. Reproduction (Cambridge, England) 67 17244754
2020 Viperin: An ancient radical SAM enzyme finds its place in modern cellular metabolism and innate immunity. The Journal of biological chemistry 66 32546482
2018 Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway. Cell death & disease 66 30068989
2018 Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin. Virology 65 30036788
2019 A key anti-viral protein, RSAD2/VIPERIN, restricts the release of measles virus from infected cells. Virus research 63 30684519
2019 Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense. Molecular cell 62 31812350
2012 In vivo and in vitro studies on the antiviral activities of viperin against influenza H1N1 virus infection. The Journal of general virology 62 22377585
2012 Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication. Journal of virology 61 22896602
2000 Vesicular stomatitis virus and pseudorabies virus induce a vig1/cig5 homologue in mouse dendritic cells via different pathways. The Journal of general virology 61 11038379
2017 Inhibition of PRMT5 suppresses osteoclast differentiation and partially protects against ovariectomy-induced bone loss through downregulation of CXCL10 and RSAD2. Cellular signalling 57 28302565
2005 The antiviral cytomegalovirus inducible gene 5/viperin is expressed in atherosclerosis and regulated by proinflammatory agents. Arteriosclerosis, thrombosis, and vascular biology 54 15890971
2014 Fish viperin exerts a conserved antiviral function through RLR-triggered IFN signaling pathway. Developmental and comparative immunology 53 25058853
2019 Viperin interacts with the kinase IRAK1 and the E3 ubiquitin ligase TRAF6, coupling innate immune signaling to antiviral ribonucleotide synthesis. The Journal of biological chemistry 49 30872404
2004 Molecular cloning of the viperin gene and its promoter region from the mandarin fish Siniperca chuatsi. Veterinary immunology and immunopathology 47 15350746
2016 Viperin inhibits rabies virus replication via reduced cholesterol and sphingomyelin and is regulated upstream by TLR4. Scientific reports 46 27456665
2010 Viperin is highly induced in neutrophils and macrophages during acute and chronic lymphocytic choriomeningitis virus infection. Journal of immunology (Baltimore, Md. : 1950) 45 20410488
2007 Induction of antiviral genes, Mx and vig-1, by dsRNA and Chum salmon reovirus in rainbow trout monocyte/macrophage and fibroblast cell lines. Fish & shellfish immunology 45 17368049
2017 Viperin Targets Flavivirus Virulence by Inducing Assembly of Noninfectious Capsid Particles. Journal of virology 44 29046456
2018 A unifying view of the broad-spectrum antiviral activity of RSAD2 (viperin) based on its radical-SAM chemistry. Metallomics : integrated biometal science 42 29568838
2018 Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin. Journal of neuroinflammation 39 29544502
2014 Rock bream (Oplegnathus fasciatus) viperin is a virus-responsive protein that modulates innate immunity and promotes resistance against megalocytivirus infection. Developmental and comparative immunology 38 24525178
2022 Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication. Molecular cell 36 35316659
2019 Intrinsic expression of viperin regulates thermogenesis in adipose tissues. Proceedings of the National Academy of Sciences of the United States of America 36 31341090
2014 Equine viperin restricts equine infectious anemia virus replication by inhibiting the production and/or release of viral Gag, Env, and receptor via distortion of the endoplasmic reticulum. Journal of virology 36 25122784
2020 ddhCTP produced by the radical-SAM activity of RSAD2 (viperin) inhibits the NAD+ -dependent activity of enzymes to modulate metabolism. FEBS letters 35 32232843
2017 Cellular requirements for iron-sulfur cluster insertion into the antiviral radical SAM protein viperin. The Journal of biological chemistry 35 28615450
2022 The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression. The Journal of clinical investigation 34 36227691
2022 Huc-MSCs-derived exosomes attenuate neuropathic pain by inhibiting activation of the TLR2/MyD88/NF-κB signaling pathway in the spinal microglia by targeting Rsad2. International immunopharmacology 34 36516531
2019 Viperin controls chikungunya virus-specific pathogenic T cell IFNγ Th1 stimulation in mice. Life science alliance 33 30665948
2010 Differential regulation of Sciaenops ocellatus viperin expression by intracellular and extracellular bacterial pathogens. Fish & shellfish immunology 33 20420911
2020 Viperin binds STING and enhances the type-I interferon response following dsDNA detection. Immunology and cell biology 31 33131099
2016 Monkey Viperin Restricts Porcine Reproductive and Respiratory Syndrome Virus Replication. PloS one 31 27232627
2018 Viperin Inhibits Enterovirus A71 Replication by Interacting with Viral 2C Protein. Viruses 30 30587778
2012 The function and evolution of the restriction factor Viperin in primates was not driven by lentiviruses. Retrovirology 30 22734835
2010 Viperin mRNA is a novel target for the human RNase MRP/RNase P endoribonuclease. Cellular and molecular life sciences : CMLS 30 21053045
2018 Grouper viperin acts as a crucial antiviral molecule against iridovirus. Fish & shellfish immunology 29 30584907
2014 Characterisation of chicken viperin. Molecular immunology 29 25311379
2023 Eukaryotic CD-NTase, STING, and viperin proteins evolved via domain shuffling, horizontal transfer, and ancient inheritance from prokaryotes. PLoS biology 28 38064485
2020 Viperin, through its radical-SAM activity, depletes cellular nucleotide pools and interferes with mitochondrial metabolism to inhibit viral replication. FEBS letters 28 32061099
2017 Viperin interaction with mitochondrial antiviral signaling protein (MAVS) limits viperin-mediated inhibition of the interferon response in macrophages. PloS one 28 28207838
2020 Structural Basis of the Substrate Selectivity of Viperin. Biochemistry 27 31917549
2019 The Interaction Mechanism Between Herpes Simplex Virus 1 Glycoprotein D and Host Antiviral Protein Viperin. Frontiers in immunology 27 31921110
2017 The radical-SAM enzyme Viperin catalyzes reductive addition of a 5'-deoxyadenosyl radical to UDP-glucose in vitro. FEBS letters 27 28752893
2016 Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity? The Journal of biological chemistry 26 27834682
2010 Phylogenetic studies of sinipercid fish (Perciformes: Sinipercidae) based on multiple genes, with first application of an immune-related gene, the virus-induced protein (viperin) gene. Molecular phylogenetics and evolution 26 20138219
2018 Viperin Deficiency Promotes Polarization of Macrophages and Secretion of M1 and M2 Cytokines. Immune network 25 30181920
2021 Knockdown of RSAD2 attenuates B cell hyperactivity in patients with primary Sjögren's syndrome (pSS) via suppressing NF-κb signaling pathway. Molecular and cellular biochemistry 24 33512636
2021 Structural Insight into the Substrate Scope of Viperin and Viperin-like Enzymes from Three Domains of Life. Biochemistry 23 34156827
2020 Targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex. The Journal of biological chemistry 22 31980458
2018 RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5' Nontranslated Regions. Journal of virology 22 29263272
2017 The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication. Virology 22 29202415
2020 Mechanism of Diol Dehydration by a Promiscuous Radical-SAM Enzyme Homologue of the Antiviral Enzyme Viperin (RSAD2). Chembiochem : a European journal of chemical biology 21 31951306
2019 Characterization and Transcript Expression Analyses of Atlantic Cod Viperin. Frontiers in immunology 21 30894853
2017 Detection of Host Response to Viral Respiratory Infection by Measurement of Messenger RNA for MxA, TRIM21, and Viperin in Nasal Swabs. The Journal of infectious diseases 21 28968760
2021 The antiviral enzyme viperin inhibits cholesterol biosynthesis. The Journal of biological chemistry 20 34029588
2019 Molecular characterization and expression analysis of rockfish (Sebastes schlegelii) viperin, and its ability to enervate RNA virus transcription and replication in vitro. Fish & shellfish immunology 20 31252045
2019 Viperin inhibits classical swine fever virus replication by interacting with viral nonstructural 5A protein. Journal of medical virology 20 31517388
2019 The interferon stimulated gene viperin, restricts Shigella. flexneri in vitro. Scientific reports 20 31666594
2017 Porcine Viperin protein inhibits the replication of classical swine fever virus (CSFV) in vitro. Virology journal 20 29061156
2010 The coiled-coil protein VIG1 is essential for tethering vacuoles to mitochondria during vacuole inheritance of Cyanidioschyzon merolae. The Plant cell 20 20348431
2024 Viperin immunity evolved across the tree of life through serial innovations on a conserved scaffold. Nature ecology & evolution 19 38965412
2021 Viperin, an IFN-Stimulated Protein, Delays Rotavirus Release by Inhibiting Non-Structural Protein 4 (NSP4)-Induced Intrinsic Apoptosis. Viruses 19 34372530
2016 miR-200 family promotes podocyte differentiation through repression of RSAD2. Scientific reports 19 27251424
2015 Identification and functional characterization of viperin of amphioxus Branchiostoma japonicum: Implications for ancient origin of viperin-mediated antiviral response. Developmental and comparative immunology 19 26190498
2017 Molecular characterization and expression analyses of the Viperin gene in Larimichthys crocea (Family: Sciaenidae). Developmental and comparative immunology 18 29066399
2021 The Antiviral Enzyme, Viperin, Activates Protein Ubiquitination by the E3 Ubiquitin Ligase, TRAF6. Journal of the American Chemical Society 17 33779167
2020 Interactions between Viperin, Vesicle-Associated Membrane Protein A, and Hepatitis C Virus Protein NS5A Modulate Viperin Activity and NS5A Degradation. Biochemistry 17 31977203
2019 The antiviral protein viperin regulates chondrogenic differentiation via CXCL10 protein secretion. The Journal of biological chemistry 17 30718282
2018 The Role of Viperin in Antiflavivirus Responses. DNA and cell biology 17 30059238
2024 Crucial Roles of RSAD2/viperin in Immunomodulation, Mitochondrial Metabolism and Autoimmune Diseases. Inflammation 16 38909344
2022 The rise of viperin: the emerging role of viperin in cancer progression. The Journal of clinical investigation 16 36519538
2015 Molecular characterization and expression analysis of the duck viperin gene. Gene 16 26049096

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