{"doi":"10.1101/2025.09.06.674652","title":"Epstein-Barr Virus Latent Membrane Protein 1 targets cIAP1, cIAP2 and TRAF2 for Proteasomal Degradation to Activate the Non-canonical NF-κB Pathway","abstract":"The Epstein-Barr virus oncoprotein Latent Membrane Protein 1 (LMP1) is expressed in multiple malignancies and is critical for B-cell immortalization. LMP1 constitutively activates NF-κB signaling pathways, which are essential for EBV-mediated B cell transformation and for transformed B cell survival. Reverse genetic analysis revealed two LMP1 regions critical for primary human B cell immortalization, termed transformation effector site (TES) 1 and 2, which activate multiple host growth and survival pathways, in particular NF-κB. Of these, only TES1 signaling is required for B-cell transformation within the first several weeks of infection. TES1 signaling is also critical for EBV-transformed lymphoblastoid B-cell survival. However, precisely how TES1 initiates NF-κB signaling has remained incompletely understood. Here, we provide multiple lines of evidence that TES1 associates with cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) in a tumor necrosis factor associated factor 3 (TRAF3) dependent manner. TES1 signaling drives cIAP1 autoubiquitination and targets TRAF2, cIAP1 and 2 for proteasomal degradation in a TRAF3 dependent manner. Overexpression of either cIAP1 or 2 impaired LMP1 TES1-mediated non-canonical NF-κB activation. Collectively, these studies suggest that LMP1 TES1 initiates non-canonical NF-κB signaling distinctly from CD40 and other host immunoreceptors, thereby highlighting a therapeutic target.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574356,"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":0.9518,"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":584824,"name":"Shunji Li","orcid":"0000-0003-1695-4899","position":1,"is_corresponding":false},{"id":393024,"name":"Bidisha Mitra","orcid":"0000-0001-6206-2723","position":2,"is_corresponding":false},{"id":1481768,"name":"Ling Zhong","orcid":"0000-0003-3551-9921","position":3,"is_corresponding":false},{"id":1482125,"name":"Aretina Zhang","orcid":null,"position":4,"is_corresponding":false},{"id":99042,"name":"Benjamin E. Gewurz","orcid":"0000-0002-3965-3418","position":5,"is_corresponding":false},{"id":1090719,"name":"Yizhe Sun","orcid":"0000-0002-5986-3826","position":0,"is_corresponding":true}],"reference_count":105,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":"40950096","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":[]}