{"doi":"10.1101/683292","title":"Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Interferons (IFNs) induce the expression of many interferon stimulated genes (ISGs), many of which are responsible for the cellular ‘antiviral state’ in which the replication of numerous viruses is blocked. How the majority of individual ISGs inhibit the replication of particular viruses is unknown. We conducted a loss-of-function screen to identify genes required for the activity of IFN\n                  <jats:italic>α</jats:italic>\n                  against vesicular stomatitis virus, Indiana serotype (VSV\n                  <jats:sub>IND</jats:sub>\n                  ), a prototype negative strand RNA virus. Our screen revealed that TRIM69, a member of tripartite motif family of proteins, is a VSV\n                  <jats:sub>IND</jats:sub>\n                  inhibitor. TRIM69 potently inhibited VSV\n                  <jats:sub>IND</jats:sub>\n                  replication through a previously undescribed transcriptional inhibition mechanism. Specifically, TRIM69 physically associates with the VSV\n                  <jats:sub>IND</jats:sub>\n                  phosphoprotein (P), requiring a specific peptide target sequence encoded therein. P is a cofactor for the viral polymerase, and is required for viral RNA synthesis as well as the assembly of replication compartments. By targeting P, TRIM69 inhibits pioneer transcription of the incoming virion-associated minus strand RNA, thereby preventing the synthesis of viral mRNAs, and consequently impedes all downstream events in the VSV\n                  <jats:sub>IND</jats:sub>\n                  replication cycle. Unlike some TRIM proteins, TRIM69 does not inhibit viral replication by inducing degradation of target viral proteins. Rather, higher-order TRIM69 multimerization is required for its antiviral activity, suggesting that TRIM69 functions by sequestration or anatomical disruption of the viral machinery required for VSV\n                  <jats:sub>IND</jats:sub>\n                  RNA synthesis.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE STATEMENT</jats:title>\n                  <jats:p>Interferons are important antiviral cytokines that work by inducing hundreds of host genes whose products inhibit replication of many viruses. While the antiviral activity of interferon has long been known, the identities and mechanisms of action of most interferon-induced antiviral proteins remain to be discovered. We identified gene products that are important for the antiviral activity of interferon against vesicular stomatitis virus (VSV) a model virus that whose genome consists a single RNA molecule with negative sense polarity. We found that a particular antiviral protein, TRIM69, functions by a previously undescribed molecular mechanism. Specifically, TRIM69 interacts with, and inhibits the function, of a particular phosphoprotein (P) component the viral transcription machinery, preventing the synthesis of viral messenger RNAs.</jats:p>\n                </jats:sec>","journal":null,"year":null,"id":599928,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"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":226293,"name":"Louis-Marie Bloyet","orcid":"0000-0002-5648-3190","position":1,"is_corresponding":false},{"id":1440708,"name":"Elena Cassella","orcid":"0000-0002-1291-1130","position":2,"is_corresponding":false},{"id":773853,"name":"Trinity Zang","orcid":"0000-0003-3931-4704","position":3,"is_corresponding":false},{"id":104730,"name":"Fabian Schmidt","orcid":"0000-0001-7731-6685","position":4,"is_corresponding":false},{"id":428105,"name":"Vesna Brusic","orcid":"0000-0002-8447-3520","position":5,"is_corresponding":false},{"id":1537750,"name":"Gergely Tekes","orcid":null,"position":6,"is_corresponding":false},{"id":255584,"name":"Owen Pornillos","orcid":"0000-0001-9056-5002","position":7,"is_corresponding":false},{"id":103752,"name":"Sean P. J. Whelan","orcid":"0000-0003-1564-8590","position":8,"is_corresponding":false},{"id":16992,"name":"Paul D. Bieniasz","orcid":"0000-0002-2368-3719","position":9,"is_corresponding":false},{"id":1537740,"name":"Tonya Kueck","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Interferons (IFNs) induce the expression of many interferon stimulated genes (ISGs), many of which are responsible for the cellular ‘antiviral state’ in which the replication of numerous viruses is blocked. How the majority of individual ISGs inhibit the replication of particular viruses is unknown. We conducted a loss-of-function screen to identify genes required for the activity of IFN\n                  <jats:italic>α</jats:italic>\n                  against vesicular stomatitis virus, Indiana serotype (VSV\n                  <jats:sub>IND</jats:sub>\n                  ), a prototype negative strand RNA virus. Our screen revealed that TRIM69, a member of tripartite motif family of proteins, is a VSV\n                  <jats:sub>IND</jats:sub>\n                  inhibitor. TRIM69 potently inhibited VSV\n                  <jats:sub>IND</jats:sub>\n                  replication through a previously undescribed transcriptional inhibition mechanism. Specifically, TRIM69 physically associates with the VSV\n                  <jats:sub>IND</jats:sub>\n                  phosphoprotein (P), requiring a specific peptide target sequence encoded therein. P is a cofactor for the viral polymerase, and is required for viral RNA synthesis as well as the assembly of replication compartments. By targeting P, TRIM69 inhibits pioneer transcription of the incoming virion-associated minus strand RNA, thereby preventing the synthesis of viral mRNAs, and consequently impedes all downstream events in the VSV\n                  <jats:sub>IND</jats:sub>\n                  replication cycle. Unlike some TRIM proteins, TRIM69 does not inhibit viral replication by inducing degradation of target viral proteins. Rather, higher-order TRIM69 multimerization is required for its antiviral activity, suggesting that TRIM69 functions by sequestration or anatomical disruption of the viral machinery required for VSV\n                  <jats:sub>IND</jats:sub>\n                  RNA synthesis.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE STATEMENT</jats:title>\n                  <jats:p>Interferons are important antiviral cytokines that work by inducing hundreds of host genes whose products inhibit replication of many viruses. While the antiviral activity of interferon has long been known, the identities and mechanisms of action of most interferon-induced antiviral proteins remain to be discovered. We identified gene products that are important for the antiviral activity of interferon against vesicular stomatitis virus (VSV) a model virus that whose genome consists a single RNA molecule with negative sense polarity. We found that a particular antiviral protein, TRIM69, functions by a previously undescribed molecular mechanism. Specifically, TRIM69 interacts with, and inhibits the function, of a particular phosphoprotein (P) component the viral transcription machinery, preventing the synthesis of viral messenger RNAs.</jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23304386","pmcid":null,"openalex_id":"https://openalex.org/W2955520530","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"3R01GM112508-03S1","title":"Structural Virology of Tripartite Motif Proteins"},{"funder_name":"National Institutes of Health","grant_id":"5R37AI059371-15","title":"RNA Processing in Non-Segmented Minus-Strand RNA Viruses"},{"funder_name":"National Institutes of Health","grant_id":"5R37AI064003-10","title":"Discovery and Mechanism of Antiretroviral Factors"}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2019,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/06/27/683292.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/06/27/683292.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/683292","host_type":"publisher"},{"url":"https://doi.org/10.1101/683292","host_type":"repository"},{"url":"https://jvi.asm.org/content/jvi/93/24/e01372-19.full.pdf","host_type":""},{"url":"https://doi.org/10.1128/jvi.01372-19","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/31578292","host_type":""},{"url":"http://dx.doi.org/10.1128/JVI.01372-19","host_type":""},{"url":"https://dx.doi.org/10.1128/jvi.01372-19","host_type":""},{"url":"https://dx.doi.org/10.1101/683292","host_type":""},{"url":"http://dx.doi.org/10.1101/683292","host_type":""}],"fields_of_study":["interferon and immune responses","Viral Infections and Vectors","Herpesvirus Infections and Treatments","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["Vesicular stomatitis virus","Biology","Viral replication","Interferon","Virology","Rhabdoviridae","Transcription (linguistics)","Antiviral protein","Virus","RNA","Gene","Cell biology","Genetics","Models, Molecular","Protein Conformation","Ubiquitin-Protein Ligases","Interferon-alpha","Vesiculovirus","Phosphoproteins","Virus Replication","Antiviral Agents","Vesicular stomatitis Indiana virus","Virus-Cell Interactions","Cell Line","Tripartite Motif Proteins","Viral Proteins","Protein Domains","Cytokines","Humans","RNA, Viral","RNA, Messenger","Vesicular Stomatitis"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T11:42:11.615551Z","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":[]}