RSAD2 encodes viperin (also called cig5 or SAND, S-adenosylmethionine-dependent nucleotide dehydratase), an interferon-inducible radical S-adenosyl-L-methionine (SAM) enzyme of the innate antiviral response. Viperin binds a single [4Fe-4S] cluster through the cysteines of a CX3CX2C motif (Cys83/Cys87/Cys90) together with an exchangeable SAM molecule, and uses the resulting 5'-deoxyadenosyl radical to dehydrate cytidine triphosphate, converting CTP to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) with release of 5'-deoxyadenosine and L-methionine. ddhCTP is a diffusible chain terminator for the RNA-dependent RNA polymerases of flaviviruses such as dengue, West Nile, Zika and hepatitis C virus, so viperin inhibits viral genome synthesis through the small molecule it makes rather than by acting on the polymerase itself; picornavirus polymerases are comparatively insensitive, and additional, interaction-based antiviral mechanisms have been described for several viruses. The protein is a peripheral membrane protein anchored by an N-terminal amphipathic helix (residues 1-42) to the cytosolic face of the endoplasmic reticulum and to lipid droplets, which are also the assembly and replication sites of many viruses; during infection it is redistributed to the Golgi apparatus and, when bound by the human cytomegalovirus protein vMIA/UL37, to mitochondria, where its interaction with the trifunctional protein lowers ATP output and paradoxically benefits that virus. Independently of catalysis, viperin acts as a scaffold in TLR7/TLR9 signalling in plasmacytoid dendritic cells, recruiting IRAK1 and TRAF6 to lipid bodies and promoting K63-linked ubiquitination of IRAK1 and IRF7-driven type I interferon production; reciprocally, IRAK1 and TRAF6 stimulate its CTP dehydratase activity about tenfold. Further, less direct roles reported in mouse include facilitation of T-cell-receptor-driven GATA3 activation and optimal T-helper 2 cytokine production in CD4+ T cells. Viperin levels are controlled by HAT1-mediated acetylation of Lys197 followed by UBE4A-dependent Lys6-linked polyubiquitination of Lys206 and proteasomal degradation.
Definition: Catalysis of the reaction: CTP + AH2 + S-adenosyl-L-methionine = 3'-deoxy-3',4'-didehydro-CTP + 5'-deoxyadenosine + L-methionine + A + H2O + H+. The reaction proceeds by radical S-adenosyl-L-methionine chemistry: a [4Fe-4S] cluster reductively cleaves S-adenosyl-L-methionine to a 5'-deoxyadenosyl radical, which abstracts the 4'-hydrogen of the CTP ribose and allows loss of the 3'-hydroxyl group, yielding the 3'-deoxy-3',4'-didehydro product without rearrangement of the carbon skeleton.
Justification: This is the physiological activity of viperin/RSAD2 (EC 4.2.-.-, RHEA:65944), the source of the antiviral chain terminator ddhCTP, and the activity for which the protein was renamed S-adenosylmethionine-dependent nucleotide dehydratase (SAND). GO has no matching term: QuickGO and OLS searches for "ddhCTP", "CTP dehydratase", "didehydro-CTP" and "nucleotide dehydratase" (checked 2026-10-18) return no candidate, so the only available annotation is the root GO:0003824 catalytic activity. The term should sit under GO:0016836 hydro-lyase activity, beside the other radical-SAM dehydratase-type activities.
Parent term: hydro-lyase activity
Mappings:
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Root-level catalytic activity from InterPro2GO radical-SAM signatures. Viperin is a bona fide enzyme whose reaction is known in detail: it dehydrates CTP to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) using SAM and a [4Fe-4S] cluster (PMID:29925952, PMID:30872404). Reason: Following the RADICAL_SAM project rule for generic rows, the specific reaction the gene is shown to catalyse should replace GO:0003824. GO currently has no term for the CTP to ddhCTP dehydration (QuickGO/OLS searches for "ddhCTP", "CTP dehydratase" and "didehydro-CTP" return nothing), so the replacement is the new term requested in proposed_new_terms; its proposed parent is GO:0016836 hydro-lyase activity. Proposed replacements: S-adenosyl-L-methionine-dependent CTP dehydratase activity (CTP to 3'-deoxy-3',4'-didehydro-CTP) Supporting Evidence: PMID:29925952 all available NMR and MS data are consistent with the Rvip-catalyzed conversion of CTP to 3′-deoxy-3′,4′-didehydro-cytidine triphosphate (ddhCTP) file:human/RSAD2/RSAD2-uniprot.txt Reaction=CTP + AH2 + S-adenosyl-L-methionine = 3'-deoxy-3',4'- |
| GO:0005515 protein binding | IPI PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | REMOVE | Summary: Interaction with human cytomegalovirus protein vMIA/UL37 (P16778), which relocalizes viperin from the ER to mitochondria during HCMV infection (PMID:21527675). The interaction is well supported, but "protein binding" states no molecular function. Reason: Per repository policy, generic GO:0005515 annotations are uninformative and are removed; the cited paper supports a virus-driven relocalization, not a specific molecular function of viperin, so no replacement term can be justified. Removal does not dispute the reported vMIA interaction, which is retained in the narrative description and in the mitochondrial-localization rows. Supporting Evidence: PMID:21527675 the viral protein vMIA resulted in viperin relocalization from the endoplasmic |
| GO:0005515 protein binding | IPI PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | REMOVE | Summary: Interaction with HADHB, the beta subunit of the mitochondrial trifunctional protein, after vMIA-driven relocalization of viperin to mitochondria; the interaction reduces ATP generation (PMID:21527675). Reason: Generic protein binding carries no functional information. The paper supports a physical interaction and a downstream metabolic consequence, but not an independent molecular function of viperin that a more informative MF term could capture. Removal does not dispute the interaction. Supporting Evidence: PMID:21527675 viperin interacted with the mitochondrial |
| GO:0005515 protein binding | IPI PMID:21957124 Viperin inhibits hepatitis C virus replication by interferin... | REMOVE | Summary: Interaction with VAPA/hVAP-33 through the viperin C-terminus; viperin competes with HCV NS5A for VAPA, which is how it limits HCV replication in this model (PMID:21957124). Reason: Uninformative generic term. The functional content of this experiment is captured by the accepted GO:0045071 negative regulation of viral genome replication row from the same paper; inventing a specific MF (e.g. an adaptor activity) from competitive co-immunoprecipitation alone is not warranted. Removal does not dispute the VAPA interaction. Supporting Evidence: PMID:21957124 interact competitively with hVAP-33, and could therefore interfere with its |
| GO:0005515 protein binding | IPI PMID:22045669 The antiviral protein viperin inhibits hepatitis C virus rep... | REMOVE | Summary: Second, independent demonstration of the viperin-VAPA association, here at the HCV replication complex together with NS5A at the lipid-droplet interface (PMID:22045669). Reason: Same policy as the other GO:0005515 rows: the generic term adds no functional information. The informative content of this paper is retained in the lipid droplet and antiviral rows. Removal does not dispute the interaction. Supporting Evidence: PMID:22045669 viperin localizes and interacts with HCV nonstructural protein 5A (NS5A) at the |
| GO:0005515 protein binding | IPI PMID:24245804 Viperin is an iron-sulfur protein that inhibits genome synth... | REMOVE | Summary: Interaction with CIAO1, a component of the cytosolic iron-sulfur protein assembly (CIA) targeting complex, required for maturation of the viperin [4Fe-4S] cluster; C-terminal truncations that cannot bind CIAO1 are not matured and are antivirally inactive (PMID:24245804). Reason: Generic protein binding is uninformative, and here it would also be misleading as a molecular function: viperin is the client of CIA-mediated cluster insertion, not the possessor of a new activity. The functional consequence is already captured by the GO:0051539 4Fe-4S cluster binding rows. Removal does not dispute the CIAO1 interaction. Supporting Evidence: PMID:24245804 inhibits productionof the viral genome RNA. Wt viperin was found to require ER |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: APOC1 hit from the HuRI systematic yeast two-hybrid binary interactome map (PMID:32296183). Reason: Generic protein binding from a high-throughput binary screen; no functional information, and no follow-up evidence links apolipoprotein C-I to viperin biology. Removal does not assert that the interaction was not observed. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: APOC4 hit from the HuRI systematic binary interactome map (PMID:32296183). Reason: Generic, uninformative term from a high-throughput screen with no functional follow-up. Removal does not assert that the interaction was not observed. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: RHBDD2 isoform hit from the HuRI systematic binary interactome map (PMID:32296183). RHBDD2 is an ER membrane rhomboid-like protein, so co-compartmentalization is plausible, but no function follows from the pairing. Reason: Generic, uninformative term from a high-throughput screen with no functional follow-up. Removal does not assert that the interaction was not observed. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic propagation of mitochondrial localization within the viperin clade, seeded in part by the human experimental annotation. Mitochondrial viperin is real but is the product of infection-driven relocalization: HCMV vMIA/UL37 binding moves viperin from the ER to mitochondria (PMID:21527675). Reason: The claim is not false, and the IBD node placement is consistent with the human IDA, so it should not be removed. However this is a conditional, virus-coopted location rather than the site where viperin normally acts, which is the cytosolic face of the ER and lipid droplets (PMID:19074433, PMID:30872404). Kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002724426 SUPPORTS TRANSFER Ancestral node for the viperin/RSAD2 clade; the human IDA from PMID:21527675 is among the descendant evidences supporting the node, so the target's own appearance in WITH/FROM is expected rather than circular. Supporting Evidence: PMID:21527675 the viral protein vMIA resulted in viperin relocalization from the endoplasmic |
| GO:0005739 mitochondrion | IDA PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | KEEP AS NON CORE | Summary: Direct microscopy in HCMV-infected cells showing viperin at mitochondria, where it binds the mitochondrial trifunctional protein and reduces ATP generation (PMID:21527675). Reason: Sound experimental observation, but conditional on HCMV vMIA expression; the resting localization is ER membrane and lipid droplets. Retained as a non-core location. Supporting Evidence: PMID:21527675 viperin interacted with the mitochondrial |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrion from the UniProt subcellular-location mapping, which records Mitochondrion for RSAD2 on the basis of the HCMV relocalization work. Reason: Consistent with the experimental row above and not false, but an infection-conditional location rather than the core site of action. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt results in its relocalization from the endoplasmic reticulum |
| GO:0005741 mitochondrial outer membrane | IDA PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | KEEP AS NON CORE | Summary: Sub-mitochondrial assignment from the same HCMV study. vMIA/UL37 is an outer membrane protein, so an outer-membrane pool of relocalized viperin is the expected topology for a peripheral, cytosol-facing protein (PMID:21527675). Reason: Plausible and curator-asserted from the full text; not disputed. Still an infection-conditional location, so non-core. Supporting Evidence: PMID:21527675 the viral protein vMIA resulted in viperin relocalization from the endoplasmic |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrion outer membrane from the UniProt subcellular-location mapping. Reason: Mirrors the experimental row; retained as a non-core, infection-conditional location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Mitochondrion outer membrane. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | KEEP AS NON CORE | Summary: Inner-membrane assignment for relocalized viperin, presumably reflecting its association with the trifunctional protein, which is an inner-membrane-associated complex (PMID:21527675). Reason: The inner-membrane claim is harder to reconcile with a peripheral, cytosol-oriented protein than the outer-membrane one, but the curator read the full text and the trifunctional-protein interaction gives it a rationale, so it is not removed. Kept as non-core and infection-conditional; see suggested_questions for the topology question. Supporting Evidence: PMID:21527675 viperin interacted with the mitochondrial |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrion inner membrane from the UniProt subcellular-location mapping, which lists the location without a publication-level evidence tag. Reason: Consistent with the experimental row; retained as non-core for the same reasons. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Mitochondrion inner |
| GO:0005783 endoplasmic reticulum | EXP PMID:16982913 TLR3 ligation activates an antiviral response in human fetal... | ACCEPT | Summary: ER localization of viperin/cig5 induced by TLR3 ligation in human fetal astrocytes (PMID:16982913). Reason: The ER is the compartment where viperin resides and acts in uninfected, interferon-stimulated cells, so this is a core location. The microscopy in this study resolves the organelle rather than the membrane leaflet, so GO:0005783 is as precise as this evidence supports; the finer GO:0005789 ER membrane claim is carried by its own accepted rows. Supporting Evidence: PMID:16982913 conclude that viperin contributes to the antiviral state induced by TLR3 |
| GO:0005783 endoplasmic reticulum | EXP PMID:30587778 Viperin Inhibits Enterovirus A71 Replication by Interacting ... | ACCEPT | Summary: Confocal microscopy placing viperin, and its complex with the enterovirus A71 2C protein, in the endoplasmic reticulum (PMID:30587778). Reason: Independent confirmation of the core ER localization. Supporting Evidence: PMID:30587778 with the EVA71 protein 2C in the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that viperin is active in the ER, seeded by the mouse and human experimental annotations. Reason: The node placement matches the experimental picture: ER targeting depends on the N-terminal amphipathic helix, which is conserved across the clade, and ER localization is required for full antiviral activity (PMID:19074433, PMID:24245804). is_active_in the ER is exactly the right claim for this gene. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002724426 SUPPORTS TRANSFER Viperin-clade ancestral node; ER targeting via the conserved N-terminal amphipathic helix is a clade-wide property, and the human gene's own experimental annotation is among the descendant evidences. Supporting Evidence: PMID:19074433 cytoplasmic face of the ER and that an amphipathic alpha-helix at its N terminus |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: ER localization from curated immunofluorescence data (GO_REF:0000052). Reason: Agrees with the primary literature on the core resting location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Endoplasmic reticulum membrane; Peripheral |
| GO:0005783 endoplasmic reticulum | IDA PMID:11752458 Viperin (cig5), an IFN-inducible antiviral protein directly ... | ACCEPT | Summary: The founding viperin paper named the protein for its ER association and showed HCMV-driven redistribution away from the ER (PMID:11752458). Reason: Original experimental evidence for the core location. Supporting Evidence: PMID:11752458 causes the redistribution of the induced viperin from its normal endoplasmic |
| GO:0005783 endoplasmic reticulum | IDA PMID:21527675 Human cytomegalovirus directly induces the antiviral protein... | ACCEPT | Summary: ER localization of viperin in the absence of vMIA, used in this study as the baseline from which HCMV relocalizes it to mitochondria (PMID:21527675). Reason: Consistent with the other ER rows; core location. Supporting Evidence: PMID:21527675 the viral protein vMIA resulted in viperin relocalization from the endoplasmic |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation of ER localization, consistent with the mouse ortholog and the UniProt subcellular-location record. Reason: Redundant with, and in agreement with, the experimental rows for the core location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Endoplasmic reticulum membrane; Peripheral |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:19074433 The N-terminal amphipathic alpha-helix of viperin mediates l... | ACCEPT | Summary: Hinson and Cresswell showed that viperin is a peripheral protein on the cytoplasmic face of the ER membrane, targeted by an N-terminal amphipathic alpha-helix that is both necessary and sufficient (PMID:19074433). Reason: This is the precise, experimentally defined core location of the enzyme and the membrane leaflet on which it faces the cytosolic CTP pool. Supporting Evidence: PMID:19074433 cytoplasmic face of the ER and that an amphipathic alpha-helix at its N terminus file:human/RSAD2/RSAD2-uniprot.txt The N-terminal region (1-42) is necessary for its localization |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment of ER membrane from the RSAD2 InterPro signature and the UniProt location vocabulary. Reason: Matches the experimentally established core location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Endoplasmic reticulum membrane; Peripheral |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1015702 | ACCEPT | Summary: Reactome's interferon-induced gene expression pathway places RSAD2 at the ER membrane. Reason: Author statement agreeing with the primary experimental evidence for the core location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Endoplasmic reticulum membrane; Peripheral |
| GO:0005794 Golgi apparatus | EXP PMID:11752458 Viperin (cig5), an IFN-inducible antiviral protein directly ... | KEEP AS NON CORE | Summary: HCMV infection redistributes viperin from the ER first to the Golgi apparatus and then to gB/pp28-containing cytoplasmic vacuoles (PMID:11752458). Reason: Experimentally observed, so not removed, but this is virus-driven redistribution rather than the compartment in which viperin normally acts. Non-core. Supporting Evidence: PMID:11752458 causes the redistribution of the induced viperin from its normal endoplasmic |
| GO:0005794 Golgi apparatus | EXP PMID:16982913 TLR3 ligation activates an antiviral response in human fetal... | KEEP AS NON CORE | Summary: Golgi signal reported alongside ER staining for viperin induced by TLR3 ligation in astrocytes (PMID:16982913). Reason: Retained on curator authority, but peripheral to the ER/lipid-droplet sites where the enzymatic and signalling functions are executed. Supporting Evidence: PMID:16982913 conclude that viperin contributes to the antiviral state induced by TLR3 |
| GO:0005794 Golgi apparatus | EXP PMID:31921110 The Interaction Mechanism Between Herpes Simplex Virus 1 Gly... | KEEP AS NON CORE | Summary: Confocal microscopy in HSV-1 infection shows viperin colocalized with glycoprotein D at the Golgi and at lipid droplets (PMID:31921110). Reason: Infection-associated localization; kept but not core. Supporting Evidence: PMID:31921110 microscopy demonstrated that gD and viperin co-localized at the Golgi body and |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi apparatus from the UniProt subcellular-location mapping, which cites the HCMV and HSV-1 studies. Reason: Consistent with the experimental rows; non-core for the same reason. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Golgi apparatus |
| GO:0005811 lipid droplet | EXP PMID:31921110 The Interaction Mechanism Between Herpes Simplex Virus 1 Gly... | ACCEPT | Summary: Viperin colocalizes with HSV-1 gD at lipid droplets (PMID:31921110); lipid droplets are also where viperin recruits IRAK1/TRAF6 in plasmacytoid dendritic cells (PMID:21435586) and where it meets HCV NS5A (PMID:22045669). Reason: Lipid droplets are one of the two constitutive sites of viperin action, targeted by the same N-terminal region that mediates ER targeting, and they are the platform for the IRAK1/TRAF6 scaffolding function. Core location. Supporting Evidence: PMID:31921110 microscopy demonstrated that gD and viperin co-localized at the Golgi body and PMID:21435586 Viperin localized to the cytoplasmic lipid-enriched |
| GO:0005811 lipid droplet | IEA GO_REF:0000120 | ACCEPT | Summary: Automated lipid-droplet assignment supported by the mouse ortholog and the RSAD2 InterPro signature. Reason: Agrees with the human and mouse experimental evidence for this core location. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt The N-terminal region (1-42) is necessary for its localization |
| GO:0005811 lipid droplet | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of the mouse viperin (Q8CBB9) lipid-droplet localization, which was established in plasmacytoid dendritic cells (PMID:21435586). Reason: The N-terminal targeting determinant is conserved and human viperin has been observed at lipid droplets directly (PMID:22045669, PMID:31921110), so the transfer is sound. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin, experimentally localized to lipid bodies in pDCs (PMID:21435586); the human protein has since been seen at lipid droplets directly, so the transfer is corroborated rather than merely inferred. Supporting Evidence: PMID:21435586 Viperin localized to the cytoplasmic lipid-enriched |
| GO:0009615 response to virus | IDA PMID:21957124 Viperin inhibits hepatitis C virus replication by interferin... | TOO GENERAL | Summary: Viperin expression limits HCV replication in replicon and HCVcc systems (PMID:21957124), which is a true statement of involvement in the response to virus. Reason: The claim is correct but uninformative here, because the more specific GO:0051607 defense response to virus (accepted on five rows, including three IDAs) is a direct is_a descendant of GO:0009615 and already entails it, as does the accepted GO:0045071. Judged on the term, not on this row's evidence. |
| GO:0009615 response to virus | IEA GO_REF:0000107 | TOO GENERAL | Summary: Automated ortholog transfer of response to virus from mouse viperin. Reason: True but entailed by the accepted, more specific GO:0051607 defense response to virus rows; consistent with the action taken on the IDA row for the same term. |
| GO:0034157 positive regulation of toll-like receptor 7 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Automated transfer from mouse viperin, where knockout reduces TLR7-induced type I interferon production in plasmacytoid dendritic cells and viperin recruits IRAK1 and TRAF6 to lipid bodies to drive K63-linked IRAK1 ubiquitination (PMID:21435586). The human protein performs the same work: TRAF6-mediated IRAK1 ubiquitination requires viperin association with both partners, and does not require catalytic activity (PMID:30872404). Reason: This is a second, genuine function of viperin, separable from its catalysis, and it is grounded in human reconstitution experiments as well as the mouse knockout. The gene product does the work of the step - it positions the kinase and the E3 ligase at lipid bodies - rather than merely being required downstream. Supporting Evidence: PMID:21435586 mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated PMID:30872404 TRAF6-mediated ubiquitination of IRAK1 requires the association of viperin with both IRAK1 and TRAF6 |
| GO:0034157 positive regulation of toll-like receptor 7 signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of the same mouse function to human RSAD2. Reason: Sound transfer, independently corroborated in human cells (PMID:30872404, PMID:31921110); consistent with the IEA row for the same term. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin; the TLR7/9 scaffold function was defined by knockout in mouse pDCs (PMID:21435586) and has since been reconstituted with the human proteins (PMID:30872404). Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Also promotes TLR7 |
| GO:0034165 positive regulation of toll-like receptor 9 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: TLR9 arm of the same IRAK1/TRAF6 scaffolding function; loss of viperin reduces both TLR7- and TLR9-induced type I interferon in pDCs (PMID:21435586). Reason: Same reasoning as the TLR7 rows: viperin executes the recruitment step, the effect is specific to the TLR7/9-IRAK1 axis (nucleic-acid-sensor-driven interferon is unaffected), and the mechanism has been reconstituted with human proteins. Supporting Evidence: PMID:21435586 Loss of Viperin reduced TLR7- and TLR9-mediated file:human/RSAD2/RSAD2-uniprot.txt Also promotes TLR7 |
| GO:0034165 positive regulation of toll-like receptor 9 signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of the mouse TLR9 function to human RSAD2. Reason: Consistent with the IEA row and with the human IRAK1/TRAF6 reconstitution data. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin knockout in pDCs established the TLR9 requirement (PMID:21435586). Supporting Evidence: PMID:30872404 TRAF6-mediated ubiquitination of IRAK1 requires the association of viperin with both IRAK1 and TRAF6 |
| GO:0035710 CD4-positive, alpha-beta T cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from mouse, where viperin-deficient CD4+ T cells show normal proliferation and IL-2 but impaired GATA3 activation and reduced NF-kB1/p50 and AP-1/JunB DNA binding after TCR engagement (PMID:19047684). Reason: A real but modulatory contribution: the activation program itself proceeds (normal anti-TCR proliferation and IL-2), with the defect confined to Th2-skewing transcription factors. Peripheral to the antiviral enzyme and signalling-scaffold functions, and established only in mouse, so kept as non-core rather than accepted as core. Supporting Evidence: PMID:19047684 GATA-3 activation and optimal Th2 cytokine production by modulating NF-kappaB |
| GO:0035710 CD4-positive, alpha-beta T cell activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of the same mouse T-cell phenotype. Reason: Consistent with the IEA row; a pleiotropic immunological role rather than a core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin knockout T cells (PMID:19047684); no equivalent human experiment exists, which is why the row is kept as non-core. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Plays a role in CD4+ T-cells |
| GO:0043367 CD4-positive, alpha-beta T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Th2 differentiation of viperin-deficient naive mouse T cells is impaired under strong TCR signalling with minimal IL-4, but not under optimal Th2-skewing conditions (PMID:19047684). Reason: Condition-dependent, modulatory role in a differentiation program driven by other factors; non-core, and mouse-only. Supporting Evidence: PMID:19047684 produced significantly less T helper 2 (Th2) cytokines, |
| GO:0043367 CD4-positive, alpha-beta T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of the mouse Th2 differentiation phenotype. Reason: Consistent with the IEA row for the same term; peripheral to the core functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin knockout (PMID:19047684). Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Plays a role in CD4+ T-cells |
| GO:0045071 negative regulation of viral genome replication | IDA PMID:21957124 Viperin inhibits hepatitis C virus replication by interferin... | ACCEPT | Summary: Viperin inhibits HCV genome replication in replicon and HCVcc systems (PMID:21957124); the same term is supported mechanistically by inhibition of TBEV genome RNA synthesis requiring the Fe-S cluster and SAM (PMID:24245804) and by ddhCTP chain termination of flavivirus RdRps (PMID:29925952). Reason: Core process. Viperin does the work: it synthesizes the chain terminator that halts viral RNA synthesis, and antiviral activity tracks with cluster assembly and SAM availability. Supporting Evidence: PMID:24245804 entirely abolished both antiviral activity and incorporation of (55) Fe PMID:29925952 as expected for the action of chain terminators |
| GO:0045071 negative regulation of viral genome replication | IEA GO_REF:0000107 | ACCEPT | Summary: Automated transfer of the same process from mouse viperin. Reason: Agrees with the human experimental evidence; core process. Supporting Evidence: PMID:29925952 we conclude that not all RdRps are sensitive to ddhCTP |
| GO:0050709 negative regulation of protein secretion | IDA PMID:19074433 The N-terminal amphipathic alpha-helix of viperin mediates l... | MARK AS OVER ANNOTATED | Summary: Overexpressed viperin, or its N-terminal amphipathic helix fused to dsRed, reduces secretion of soluble alkaline phosphatase and bulk protein secretion and slows ER-to-Golgi transport, while membrane-protein transport is unaffected; intact viperin also induces crystalloid ER (PMID:19074433). Reason: The observation is real and the annotation is not false, so it is not removed. However the effect is a consequence of helix-driven membrane remodelling under ectopic expression - the isolated helix reproduces it, and acidifying its hydrophobic face abolishes it - rather than a dedicated secretory-regulatory role of the enzyme; UniProt states it only as a capability. Treating it as a biological process in which viperin participates overstates the evidence. Supporting Evidence: PMID:19074433 alpha-helix-dsRed fusion protein significantly reduced secretion of soluble PMID:19074433 Viperin expression also affected the transport of soluble but not |
| GO:0050778 positive regulation of immune response | IBA GO_REF:0000033 | TOO GENERAL | Summary: Phylogenetic inference of a positive immune-regulatory role, placed from the mouse TLR7/9 and T-cell data. Reason: The claim is true, but GO:0050778 is an ancestor of the accepted GO:0034157 and GO:0034165 rows (verified in QuickGO), which already entail it and say exactly which pathway viperin potentiates. Judges the term, not the IBD node placement, which is sound. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002724426 SUPPORTS TRANSFER Node placement is defensible; the issue is only that the term chosen is an ancestor of the specific TLR7/TLR9 terms also annotated. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000002 | MODIFY | Summary: Iron-sulfur cluster binding from InterPro2GO radical-SAM signatures. Viperin binds one [4Fe-4S] cluster through Cys83/Cys87/Cys90 plus an exchangeable SAM (PMID:20176015, PMID:20026307, PMID:22363738). Reason: Per the RADICAL_SAM project rule, GO:0051536 should be refined to GO:0051539, the descendant that the radical SAM cluster always satisfies and that this gene already carries by IDA and IBA. Proposed replacements: 4 iron, 4 sulfur cluster binding Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Note=Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 PMID:20026307 reconstituted the [4Fe-4S] cluster in Viperin (45-361), thus providing the first |
| GO:0051539 4 iron, 4 sulfur cluster binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of [4Fe-4S] binding from a deep radical-SAM node, with the human experimental annotation among the descendant evidences. Reason: The cluster is the catalytic cofactor of the enzyme and is required for antiviral activity (PMID:24245804), so this is a core molecular function. The node placement is appropriate: cluster binding is a defining property of the radical SAM superfamily. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000481986 SUPPORTS TRANSFER Deep radical-SAM ancestral node; cluster binding is a superfamily-wide property, and human RSAD2's own IDA (PMID:20176015) is one of the descendant evidences, which is expected rather than circular. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Belongs to the radical SAM superfamily. RSAD2 family. |
| GO:0051539 4 iron, 4 sulfur cluster binding | IDA PMID:20176015 The antiviral protein viperin is a radical SAM enzyme. | ACCEPT | Summary: Iron analysis plus UV-visible and EPR spectroscopy show that reduced viperin carries a [4Fe-4S](1+) cluster whose g-values change on SAM addition, and that it performs reductive cleavage of SAM to 5'-deoxyadenosine (PMID:20176015). Reason: Direct experimental demonstration of the core catalytic cofactor. Supporting Evidence: PMID:20176015 Incubation of reduced viperin with SAM results in reductive cleavage of SAM to PMID:22363738 The CX3CX2C motif is involved in iron-sulfur (Fe-S) cluster binding in |
| GO:0051607 defense response to virus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of antiviral defense across the viperin clade (mouse, human and zebrafish descendant evidences). Reason: Core process, and the node placement matches the biology: the enzymatic machinery (cluster, SAM, CTP substrate) and the interferon inducibility are conserved across vertebrate viperins. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002724426 SUPPORTS TRANSFER Viperin-clade node; human RSAD2's own experimental annotations are among the descendant evidences, as expected for an inherited function. Supporting Evidence: PMID:29925952 viperin is the only human protein that produces a small molecule capable of directly inhibiting viral replication machinery |
| GO:0051607 defense response to virus | IDA PMID:16108059 Analysis of ISG expression in chronic hepatitis C identifies... | ACCEPT | Summary: Viperin is one of the most strongly induced interferon-stimulated genes in chronic hepatitis C liver, and its transient expression reduces HCV replication in replicon cells (PMID:16108059). Reason: Direct evidence for the core antiviral process. Supporting Evidence: PMID:16108059 Transient expression of viperin in cells harboring the HCV PMID:16108059 viperin has anti-HCV activity in vitro |
| GO:0051607 defense response to virus | IDA PMID:16982913 TLR3 ligation activates an antiviral response in human fetal... | ACCEPT | Summary: RNAi against viperin reverses the TLR3/interferon-beta-dependent antiviral state of human fetal astrocytes against a VSV-G-pseudotyped HIV-1 particle (PMID:16982913). Reason: Loss-of-function evidence in human cells for the core antiviral process. Supporting Evidence: PMID:16982913 conclude that viperin contributes to the antiviral state induced by TLR3 |
| GO:0051607 defense response to virus | IDA PMID:9391139 Use of differential display analysis to assess the effect of... | ACCEPT | Summary: The differential-display screen that first identified cig5/RSAD2 as an interferon-responsive mRNA induced by human cytomegalovirus infection (PMID:9391139). Reason: The term is correct for the gene and is independently established by the other rows. This particular reference documents interferon-responsive induction rather than an antiviral assay, so it is weak support for involvement on its own; it is kept rather than removed because the claim is true and the curator worked from the full text (see suggested_questions on reference choice). Supporting Evidence: PMID:9391139 induced by interferon alpha |
| GO:0051607 defense response to virus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation of antiviral defense from the mouse ortholog and the RSAD2-specific InterPro signature. Reason: Redundant with, and in agreement with, the experimental and IBA rows for the core process. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Interferon-inducible antiviral protein which plays a major |
| GO:2000553 positive regulation of T-helper 2 cell cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse viperin-deficient CD4+ T cells produce significantly less IL-4, IL-5 and IL-13 after anti-CD3 stimulation, with impaired GATA3 activation (PMID:19047684). Reason: Specific and experimentally grounded in mouse, but a modulatory immunological role far downstream of the antiviral enzyme function, and not demonstrated in human cells. Non-core. Supporting Evidence: PMID:19047684 produced significantly less T helper 2 (Th2) cytokines, |
| GO:2000553 positive regulation of T-helper 2 cell cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of the mouse Th2 cytokine phenotype to human RSAD2. Reason: Consistent with the IEA row for the same term; peripheral to the core functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8CBB9 SUPPORTS TRANSFER Mouse viperin knockout (PMID:19047684); the human ortholog has not been tested in this assay. Supporting Evidence: file:human/RSAD2/RSAD2-uniprot.txt Plays a role in CD4+ T-cells |
| GO:1904047 S-adenosyl-L-methionine binding | IDA PMID:20176015 The antiviral protein viperin is a radical SAM enzyme. | NEW | Summary: SAM is the cosubstrate of viperin: EPR g-values of the reduced [4Fe-4S] cluster shift upon SAM addition, consistent with SAM coordination to the cluster, and incubation with SAM yields 5'-deoxyadenosine (PMID:20176015). UniProt records the cluster as a 4Fe-4S-S-AdoMet cluster with an exchangeable SAM, and the catalytic reaction consumes SAM. Reason: Missing molecular function for this gene. SAM binding is directly demonstrated spectroscopically and is required for the catalytic cycle; the RADICAL_SAM project treats GO:1904047 as a cosubstrate-binding term that holds for every active family member, and it is absent from the current GOA set for RSAD2. This is an MF-binding claim with direct experimental support, not a process inference. Supporting Evidence: PMID:20176015 consistent with SAM coordination to the cluster file:human/RSAD2/RSAD2-uniprot.txt /ligand_note="4Fe-4S-S-AdoMet" |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:30872404 Viperin interacts with the kinase IRAK1 and the E3 ubiquitin... | NEW | Summary: In the TLR7/TLR9 pathway viperin brings IRAK1 and TRAF6 together: in mouse pDCs it recruits both to lipid bodies and facilitates K63-linked IRAK1 ubiquitination (PMID:21435586), and in human reconstitution TRAF6-mediated IRAK1 ubiquitination requires viperin association with both partners and does not require catalytically active viperin (PMID:30872404). Reason: The scaffolding function is experimentally separable from catalysis and is the molecular activity underlying the accepted GO:0034157/GO:0034165 process rows, which currently have no corresponding molecular function. Viperin itself performs the work the term names - it binds and co-localizes the kinase and the E3 ligase so that they can act together - rather than being a substrate or a downstream requirement, and the activity survives loss of catalysis, so it is not a restatement of the enzymatic function. Supporting Evidence: PMID:30872404 TRAF6-mediated ubiquitination of IRAK1 requires the association of viperin with both IRAK1 and TRAF6 PMID:21435586 mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated file:human/RSAD2/RSAD2-uniprot.txt Interacts with IRAK1 and TRAF6 |
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Download this section (compressed HTML)Q: Is the mitochondrial inner-membrane localization of viperin (GO:0005743) compatible with a peripheral, cytosol-facing protein, or does it reflect co-fractionation with the trifunctional protein after vMIA-driven relocalization? The distinction matters because the inner-membrane row is currently indistinguishable from the outer-membrane row in the annotation set.
Suggested experts: Peter Cresswell, Jun-Young Seo
Q: Does human viperin positively regulate interferon-beta production (GO:0032728) in its own right, beyond the TLR7/TLR9 pathway-level terms already annotated? The mouse knockout and the HSV-1 gD reporter data point that way, but the pathway terms may already be the appropriate level of assertion.
Suggested experts: Tatsuya Saitoh, E Neil G Marsh
Q: Which cellular polymerases or nucleotide-pool enzymes protect the host from ddhCTP, given that viperin-expressing cells accumulate ddhCTP to about 30% of the CTP pool without loss of viability?
Suggested experts: Steven C Almo, Tyler L Grove
Q: Is the FPPS-dependent lipid-raft mechanism reported for influenza A virus release a separate function of viperin, or a downstream consequence of ddhCTP production and ER membrane remodelling? No GO process term is proposed here pending an answer.
Suggested experts: Peter Cresswell
Experiment: Complement viperin-knockout human cells with wild-type viperin, the C83A/C87A/C90A cluster-null mutant, and a localization-matched mutant retaining the N-terminal helix but lacking catalysis, then challenge with a ddhCTP-sensitive flavivirus and a ddhCTP-insensitive picornavirus while measuring intracellular ddhCTP by LC-MS. This separates catalysis-dependent from interaction-based antiviral effects virus by virus.
Hypothesis: The antiviral activity of human viperin against a given virus is proportional to the sensitivity of that virus's polymerase to ddhCTP, and is abolished by catalytically dead but correctly localized viperin.
Type: genetic complementation with metabolite quantification
Experiment: In primary human plasmacytoid dendritic cells, replace endogenous viperin with catalytically inactive (cluster-null) or IRAK1/TRAF6-binding-deficient variants and measure TLR7/TLR9-induced IFN-beta, IRAK1 K63-ubiquitination and ddhCTP levels in parallel. A clean separation would justify annotating the adaptor activity and the enzymatic activity as distinct core functions in human cells, as is currently inferred from mouse and reconstitution data.
Hypothesis: The adaptor function of viperin in TLR7/9 signalling is genetically separable from its CTP dehydratase activity.
Type: structure-function rescue in primary human cells
Experiment: Compare Th2 cytokine output and GATA3 activation in T cells from mice expressing catalytically dead versus scaffold-deficient viperin knock-in alleles, instead of the whole-gene knockout used previously. This would show whether the T-cell role should remain a non-core annotation or be mechanistically attached to one of the core functions, and whether it is expected to hold in human T cells.
Hypothesis: The CD4+ T-cell Th2 phenotype of viperin-deficient mice reflects the lipid-body scaffolding function rather than ddhCTP synthesis.
Type: knock-in mouse genetics with immunophenotyping
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