{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Dahal K"],"funding":["NIAID NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["Small interfering RNAs (siRNAs) produced through the processing of viral double-stranded RNAs mediate potent antiviral RNA interference (RNAi) in eukaryotes. In <i>Caenorhabditis elegans</i>, such an antiviral defense is further amplified through the production of secondary siRNAs, yet the mechanisms by which secondary virus-derived siRNAs (vsiRNAs) confer protection remain poorly understood. Here, we characterize the role of <i>rsd-6</i>, which encodes a Tudor domain protein and plays important role in antiviral RNAi, in vsiRNA biogenesis and modulation of viral pathogenesis. Using CRISPR Cas9-generated <i>rsd-6</i> null mutants, we show that both primary and secondary vsiRNAs accumulate normally in the absence of RSD-6, indicating that it functions downstream of secondary vsiRNA biogenesis. We further showed that secondary vsiRNAs generated in <i>rrf-1</i>-independent manner remained detected in the absence of RSD-6 and viral replication is further enhanced in <i>rrf-1;rsd-6</i> double mutants compared to <i>rrf-1</i> single mutants, suggesting a role of <i>rsd-6</i> in mediating antiviral guided by all secondary vsiRNAs. Consistently, <i>rsd-6</i> mutants exhibited more severe pathogenesis upon Orsay virus infection compared to <i>rrf-1</i> mutants, underscoring its role as a major determinant of viral disease outcome. Domain characterization established that the N-terminal tandem domains of RSD-6 are required for antiviral activity, while the C-terminal Tudor domains are dispensable. Functional conservation was confirmed in <i>C. briggsae</i>, where silencing of the <i>rsd-6</i> homolog enhanced viral replication. Together, our findings identify RSD-6 as a key effector acting downstream of secondary vsiRNA production and highlight its conserved role in modulating viral replication and pathogenesis across <i>Caenorhabditis</i> species."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2025.09.02.673749"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12424992"],"repository":["biostudies-literature"],"pubmed_title":["Characterizing the role of RSD-6 in the biogenesis of virus-derived small interfering RNAs and the modulation of viral pathogenesis."],"pmcid":["PMC12424992"],"funding_grant_id":["R01 GM119012","R03 AI171860"],"pubmed_authors":["Dahal K","Xia M","Lu J","Yan T","Lu R"],"additional_accession":[]},"is_claimable":false,"name":"Characterizing the role of RSD-6 in the biogenesis of virus-derived small interfering RNAs and the modulation of viral pathogenesis.","description":"Small interfering RNAs (siRNAs) produced through the processing of viral double-stranded RNAs mediate potent antiviral RNA interference (RNAi) in eukaryotes. In <i>Caenorhabditis elegans</i>, such an antiviral defense is further amplified through the production of secondary siRNAs, yet the mechanisms by which secondary virus-derived siRNAs (vsiRNAs) confer protection remain poorly understood. Here, we characterize the role of <i>rsd-6</i>, which encodes a Tudor domain protein and plays important role in antiviral RNAi, in vsiRNA biogenesis and modulation of viral pathogenesis. Using CRISPR Cas9-generated <i>rsd-6</i> null mutants, we show that both primary and secondary vsiRNAs accumulate normally in the absence of RSD-6, indicating that it functions downstream of secondary vsiRNA biogenesis. We further showed that secondary vsiRNAs generated in <i>rrf-1</i>-independent manner remained detected in the absence of RSD-6 and viral replication is further enhanced in <i>rrf-1;rsd-6</i> double mutants compared to <i>rrf-1</i> single mutants, suggesting a role of <i>rsd-6</i> in mediating antiviral guided by all secondary vsiRNAs. Consistently, <i>rsd-6</i> mutants exhibited more severe pathogenesis upon Orsay virus infection compared to <i>rrf-1</i> mutants, underscoring its role as a major determinant of viral disease outcome. Domain characterization established that the N-terminal tandem domains of RSD-6 are required for antiviral activity, while the C-terminal Tudor domains are dispensable. Functional conservation was confirmed in <i>C. briggsae</i>, where silencing of the <i>rsd-6</i> homolog enhanced viral replication. Together, our findings identify RSD-6 as a key effector acting downstream of secondary vsiRNA production and highlight its conserved role in modulating viral replication and pathogenesis across <i>Caenorhabditis</i> species.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-03T03:13:11.566Z","creation":"2026-06-03T03:10:37.405Z"},"accession":"S-EPMC12424992","cross_references":{"pubmed":["40950003"],"doi":["10.1101/2025.09.02.673749"]}}