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During RNAi in\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      , the nucleotidyltransferase RDE-3 modifies the 3\u2032 termini of mRNAs with polyUG (pUG) tails, which recruit RNA-dependent RNA polymerase (RdRP) enzymes that drive gene silencing by synthesizing antisense small interfering (si)RNAs. During normal growth and development, RDE-3 pUGylates transposon RNAs to silence transposons and protect genomic integrity. How\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      identifies specific RNAs for pUGylation and whether the pUGylation system is used for other biological purposes are not yet known. Here, we show that pUGylation contributes to antiviral immunity in\n                      <jats:italic toggle=\"yes\">C. elegans:<\/jats:italic>\n                      During infection of\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      with Orsay virus, RDE-3 adds pUG tails to viral RNAs, which converts these RNAs into templates for RdRP-based antiviral siRNA production, thereby limiting viral replication. We present evidence that MUT-15 is critical for viral pUGylation because it interacts with RDE-3 and the NYN domain-containing endonuclease RDE-8, thus bridging the enzymes that cleave and pUGylate viral RNA, ensuring efficient antiviral immunity. We conclude that pUGylation promotes antiviral immunity in\n                      <jats:italic toggle=\"yes\">C. elegans,<\/jats:italic>\n                      and we provide molecular insights into how\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      identifies and neutralizes its internal and external parasitic threats.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Viruses are a threat to all organisms. Therefore, organisms have evolved numerous systems to recognize and neutralize viruses. Many of these systems, which are referred to as innate immune systems, function by recognizing unique molecular characteristics of the viral genetic material. One such innate immune system is RNA interference (RNAi). RNA interference uses double-stranded RNA, which is an obligatory byproduct of replication for many viruses, as a weapon to fight viruses. In this work, we provide molecular insights into how the nematode\n                        <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                        uses RNA interference and viral double-stranded RNAs to defend itself against viral invaders.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01169-25","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T13:00:57Z","timestamp":1761829257000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Viral RNA pUGylation promotes antiviral immunity in\n                    <i>C. elegans<\/i>"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2322-3437","authenticated-orcid":true,"given":"David D.","family":"Lowe","sequence":"first","affiliation":[{"name":"Department of Genetics, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9743-4128","authenticated-orcid":true,"given":"Aditi","family":"Shukla","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04vqm6w82","id-type":"ROR","asserted-by":"publisher"}],"name":"Whitehead Institute for Biomedical Research","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7974-8155","authenticated-orcid":true,"given":"Scott G.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03957"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.033"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307453110"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904086107"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1105\/tpc.109.072058"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111440998"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201628109"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241930"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241911"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2018100941"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03870"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.927801"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132839"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(02)00793-6"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81644-x"},{"key":"e_1_3_4_17_2","first-page":"1397","article-title":"Distinct roles for RDE-1 and RDE-4 during RNA interference in Caenorhabditis elegans","volume":"7","author":"Parrish S","year":"2001","unstructured":"Parrish S, Fire A. 2001. 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