{"doi":"10.1128/jvi.78.19.10765-10775.2004","title":"Temporal Modulation of an Autoprotease Is Crucial for Replication and Pathogenicity of an RNA Virus","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>Pestiviruses belong to the family<jats:italic>Flaviviridae</jats:italic>, and their genome is a single-stranded RNA of positive polarity encoding one large polyprotein which is further processed into mature proteins. Noncytopathogenic (noncp) strains of the pestivirus bovine viral diarrhea virus (BVDV) can establish persistent infection. In persistently infected animals, noncp BVDVs occasionally acquire mutations in viral nonstructural protein 2 (NS2) that give rise to cytopathogenic (cp) BVDV variants, and, eventually, lead to the onset of lethal disease. A molecular marker of cp BVDV infection is a high-level expression of the replicative NS3 protease/helicase that together with NS2 is derived from NS2-3. Here, we present evidence for NS2-3 autoprocessing by a newly identified cysteine protease in NS2 that is distantly related to the NS2-3 autoprotease of hepatitis C and GB viruses. The vital role of this autoprotease in BVDV infection was established, implying an essential function for NS3 in pestiviral RNA replication which cannot be supplied by its NS2-3 precursor. Accordingly, and contrary to a current paradigm, we detected almost complete cleavage of NS2-3 in noncp BVDV at early hours of infection. At 6 to 9 h postinfection, NS2-3 autoprocessing diminished to barely detectable levels for noncp BVDV but decreased only moderately for cp BVDV. Viral RNA synthesis rates strictly correlated with different NS3 levels in noncp and cp BVDV-infected cells, implicating the NS2 autoprotease in RNA replication control. The biotype-specific modulation of NS2-3 autoprocessing indicates a crucial role of the NS2 autoprotease in the pathogenicity of BVDV.</jats:p>","journal":"Journal of Virology","year":2004,"id":40124,"datarank":5.42070347083845,"base_score":5.017279836814924,"endowment":5.017279836814924,"self_citation_contribution":0.7525919755222388,"citation_network_contribution":4.668111495316211,"self_endowment_contribution":0.7525919755222388,"citer_contribution":4.668111495316211,"corpus_percentile":null,"corpus_rank":null,"citation_count":150,"citer_count":125,"citers_with_citation_signal":109,"citers_with_endowment":109,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":48.75,"fair_percentile":44.94283201407212,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":195495,"name":"A. Müller","orcid":null,"position":1,"is_corresponding":false},{"id":195496,"name":"A. Pankraz","orcid":null,"position":2,"is_corresponding":false},{"id":195497,"name":"P. Becher","orcid":null,"position":3,"is_corresponding":false},{"id":195498,"name":"H.-J. Thiel","orcid":null,"position":4,"is_corresponding":false},{"id":195499,"name":"A. E. Gorbalenya","orcid":null,"position":5,"is_corresponding":false},{"id":195500,"name":"N. Tautz","orcid":null,"position":6,"is_corresponding":false},{"id":195494,"name":"T. Lackner","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.017279836814924,"endowment":5.017279836814924,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"15367643","pmcid":"PMC516412","openalex_id":"https://openalex.org/W2168079335","authors":[],"funders":[],"total_grants":0,"fwci":16.8544,"citation_percentile":0.99583467,"influential_citations":18,"citation_trend":[{"year":2012,"count":7},{"year":2013,"count":7},{"year":2014,"count":10},{"year":2015,"count":6},{"year":2016,"count":3},{"year":2017,"count":9},{"year":2018,"count":6},{"year":2019,"count":3},{"year":2020,"count":1},{"year":2021,"count":8},{"year":2022,"count":2},{"year":2023,"count":7},{"year":2024,"count":6},{"year":2025,"count":4},{"year":2026,"count":4}],"oa_status":"green","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/516412","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc516412?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/516412","host_type":"repository"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.78.19.10765-10775.2004","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.78.19.10765-10775.2004","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/15367643","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.327.7598","host_type":""},{"url":"http://europepmc.org/pmc/articles/PMC516412","host_type":"repository"}],"fields_of_study":["Animal Disease Management and Epidemiology","Vector-Borne Animal Diseases","Viral Infections and Immunology Research","Biology","Medicine","Amino Acid Sequence","Amino Acid Substitution","Animals","Binding Sites","Cattle","Cell Line","Cricetinae","Cysteine Endopeptidases","Cytopathogenic Effect, Viral","Diarrhea Viruses, Bovine Viral","GB virus A","GB virus B","GB virus C","Hepacivirus","Molecular Sequence Data","Mutation, Missense","Peptide Hydrolases","RNA Helicases","RNA, Viral","Sequence Homology","Viral Nonstructural Proteins","Viral Proteins","Virus Replication","Serine Endopeptidases","Nucleoside-Triphosphatase","DEAD-box RNA Helicases","Viral Proteases"],"mesh_terms":["Viral Proteases","Amino Acid Sequence","Animals","Binding Sites","Diarrhea Viruses, Bovine Viral","Cattle","Cell Line","Cysteine Endopeptidases","Cytopathogenic Effect, Viral","Cricetinae","Molecular Sequence Data","Peptide Hydrolases","RNA, Viral","Serine Endopeptidases","Viral Proteins","Virus Replication","Hepacivirus","Viral Nonstructural Proteins","Sequence Homology","Amino Acid Substitution","Mutation, Missense","RNA Helicases","GB virus A","GB virus B","GB virus C","Nucleoside-Triphosphatase","DEAD-box RNA Helicases"],"keywords":["Biology","NS3","Virology","Pestivirus","Flaviviridae","Virus","Viral replication","RNA","NS2-3 protease","Hepatitis C virus","Helicase","RNA virus","Genetics","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and 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in an open repository.","Attach a clear, open reuse license (e.g. CC-BY or CC0)."],"model":null,"agent_version":"fair_agent_v1","fulltext_source":"oa_pdf"},"fair_model":null,"fair_agent_version":"fair_agent_v1","fair_fulltext_source":"oa_pdf","fair_has_llm":false,"fair_computed_at":"2026-06-12T03:43:08.834494Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}