{"doi":"10.1126/science.adw4937","title":"Poxvirus attack of antiviral defense pathways unleashes an effector-triggered NF-κB response","abstract":"<jats:p>Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or “effectors.” To discover ETI pathways in mammals, we developed a screening approach in which we expressed individual virulence factors in a human monocyte cell line and assessed transcriptional responses by RNA sequencing. We identified a poxvirus effector, myxoma virus M3.1, which elicited an antiviral nuclear factor κB (NF-κB) response. NF-κB was unleashed by an ETI pathway that sensed M3.1 attack of two antiviral complexes: zinc finger antiviral protein and TBK1. NF-κΒ activation occurred because the proteins inhibited by M3.1—N4BP1, ZC3H12A, and TBK1—are negative regulators of NF-κB. Our study established a systematic approach for the discovery of ETI pathways, and the results illustrated how negative regulators of immune responses may function in pathogen sensing.</jats:p>","journal":"Science","year":2026,"id":643758,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1465767,"name":"Joshua Q. Mao","orcid":"0009-0007-5606-8062","position":1,"is_corresponding":false},{"id":248002,"name":"Andrew G. Manford","orcid":"0000-0003-4472-9509","position":2,"is_corresponding":false},{"id":998115,"name":"Ami D. Gutierrez-Jensen","orcid":"0009-0002-5120-6845","position":3,"is_corresponding":false},{"id":6926,"name":"Allon Wagner","orcid":"0000-0001-5095-6009","position":4,"is_corresponding":false},{"id":248007,"name":"Michael Rapé","orcid":"0000-0003-4849-6343","position":5,"is_corresponding":false},{"id":388303,"name":"Grant McFadden","orcid":"0000-0002-2556-3526","position":6,"is_corresponding":false},{"id":388302,"name":"Masmudur M. Rahman","orcid":"0000-0002-7177-819X","position":7,"is_corresponding":false},{"id":556933,"name":"Moritz M. Gaidt","orcid":"0000-0002-8009-294X","position":8,"is_corresponding":false},{"id":251793,"name":"Russell E. Vance","orcid":"0000-0002-6686-3912","position":9,"is_corresponding":false},{"id":665238,"name":"Brenna C. Remick","orcid":"0000-0001-5333-6657","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Poxvirus attack of antiviral defense pathways unleashes an effector-triggered NF-κB response","abstract":"<jats:p>Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or “effectors.” To discover ETI pathways in mammals, we developed a screening approach in which we expressed individual virulence factors in a human monocyte cell line and assessed transcriptional responses by RNA sequencing. We identified a poxvirus effector, myxoma virus M3.1, which elicited an antiviral nuclear factor κB (NF-κB) response. NF-κB was unleashed by an ETI pathway that sensed M3.1 attack of two antiviral complexes: zinc finger antiviral protein and TBK1. NF-κΒ activation occurred because the proteins inhibited by M3.1—N4BP1, ZC3H12A, and TBK1—are negative regulators of NF-κB. Our study established a systematic approach for the discovery of ETI pathways, and the results illustrated how negative regulators of immune responses may function in pathogen sensing.</jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41678605","pmcid":"PMC13041778","openalex_id":"https://openalex.org/W7128690938","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"AI075039","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI155634","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI063302","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI080607","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI190589","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI100829","title":null},{"funder_name":"H2020 European Research Council","grant_id":"101117146","title":"Guard-driven immunity against pathogens"},{"funder_name":"Arizona Biomedical Research Center Investigator Award","grant_id":"RFGA2022-010-22","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"P01 AI063302","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI075039","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R37 AI075039","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R21 AI190589","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"T32 AI100829","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI080607","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI155634","title":null},{"funder_name":"Howard Hughes Medical Institute Emerging Pathogen Initiative funding","grant_id":"","title":null},{"funder_name":"Boehringer Ingelheim","grant_id":"","title":null},{"funder_name":"National Science Foundation Graduate Research Fellowship Program","grant_id":"","title":null},{"funder_name":"Howard Hughes Medical Institute Investigator award","grant_id":"","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null}],"total_grants":21,"fwci":7.5426,"citation_percentile":0.96080965,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"closed","license":"https://www.science.org/content/page/science-licenses-journal-article-reuse","oa_locations":[{"url":"https://www.science.org/doi/pdf/10.1126/science.adw4937","host_type":"publisher"},{"url":"https://doi.org/10.1126/science.adw4937","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41678605","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC13041778","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC13041778?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1101/2025.03.04.641538","host_type":""},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13041778/","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/41678605/","host_type":""},{"url":"http://dx.doi.org/10.1126/science.adw4937","host_type":""}],"fields_of_study":["interferon and immune responses","Poxvirus research and outbreaks","NF-κB Signaling Pathways","0301 basic medicine","03 medical and health sciences","Humans","Host-Pathogen Interactions","Innate Immunity Recognition","Monocytes","Myxoma virus","NF-kappa B","Protein Serine-Threonine Kinases","Viral Proteins","Virulence Factors","Zinc Fingers","Poxviridae Infections","Tumor Virus Infections","Cell Line, Tumor"],"mesh_terms":["Innate Immunity Recognition","Cell Line","Humans","Immunity, Innate","Monocytes","Myxoma virus","Poxviridae Infections","Tumor Virus Infections","Viral Proteins","Signal Transduction","NF-kappa B","Zinc Fingers","Protein Serine-Threonine Kinases","Virulence Factors","Cell Line, Tumor","Host-Pathogen Interactions"],"keywords":["Virulence","Myxoma virus","Pathogen","Immune system","Immunity","Virus","Interferon","Innate immune system","Function (biology)","Virulence Factors","NF-kappa B","Protein Serine-Threonine Kinases","Article","Monocytes","Immunity, Innate","Cell Line","Viral Proteins","Host-Pathogen Interactions","Humans","Signal Transduction"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-08T18:42:35.717807Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}