{"doi":"10.1101/2025.08.09.669493","title":"KSHV-encoded vIRF3 Cooperates with Cellular IRF4 to Drive Super-Enhancer Activity through Complex DNA Elements","abstract":"The Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein vIRF3 is essential for the survival of primary effusion lymphoma (PEL) cells. vIRF3 cooperates with cellular IRF4 to activate super-enhancers (SEs) driving oncogenes including MYC and IRF4 itself. However, the vIRF3/IRF4-responsive DNA sequences underlying this cooperation are unknown. Investigating the IRF4-SE, we mapped its vIRF3/IRF4-responsiveness to a complex ∼83 bp region, which retained cooperative activation by vIRF3 and IRF4 and was activated by vIRF3 but not IRF4 alone. vIRF3-mediated activation depended on an AP1 site, while the cooperation of vIRF3 with IRF4 required the DNA binding ability of IRF4 and IRF-related motifs that do not participate in canonical AP1-IRF (AICE) composite sites. These motifs are necessary but insufficient to confer responsiveness outside their native sequence context, suggesting that vIRF3/IRF4-mediated IRF4-SE activation requires an extended composite element. DNA pulldowns confirmed the importance of the identified motifs for association of vIRF3 and IRF4 with the IRF4-SE. A PEL MYC-SE similarly depended on an extended responsive element containing a critical AP1 site, within a functional AICE motif. Together, our results show that vIRF3 activates oncogenic SEs by co-opting complex genetic elements that may accommodate previously unknown IRF4 binding configurations, improving our understanding of vIRF3 and IRF4-dependent oncogenesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":572364,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1329360,"name":"Haocong Katherine","orcid":null,"position":1,"is_corresponding":false},{"id":1398355,"name":"Christine B. Magdongon","orcid":null,"position":2,"is_corresponding":false},{"id":855802,"name":"Maureen E. Haynes","orcid":"0000-0001-7557-4162","position":3,"is_corresponding":false},{"id":1478544,"name":"Jingyi Lu","orcid":"0000-0001-7621-7140","position":4,"is_corresponding":false},{"id":344357,"name":"Elizabeth T. Bartom","orcid":"0000-0002-5618-2582","position":5,"is_corresponding":false},{"id":1331309,"name":"Eva Gottwein","orcid":"0000-0002-4519-2259","position":6,"is_corresponding":false},{"id":1331306,"name":"Ziyan Liang","orcid":"0000-0001-7001-270X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40832199","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":[]}