{"doi":"10.4049/jimmunol.2000026","title":"The Structural Basis of IRF-3 Activation upon Phosphorylation","abstract":"Abstract The innate immune system is the first line of defense against bacterial and viral infections. The recognition of pathogen-associated molecular patterns by the RIG-I–like receptors, TLRs, and cGAS leads to the induction of IFN-I by activating the transcription factor IRF-3. Although the mechanism of IRF-3 activation has been extensively studied, the structural basis of IRF-3 activation upon phosphorylation is not fully understood. In this study, we determined the crystal structures of phosphorylated human and mouse IRF-3 bound to CREB-binding protein (CBP), which reveal that phosphorylated IRF-3 forms a dimer via pSer386 (pSer379 in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer386 severely impair IRF-3 activation and IFN-β induction. By contrast, phosphorylation of Ser396 within the pLxIS motif of human IRF-3 only plays a moderate role in IRF-3 activation. The mouse IRF-3/CBP complex structure reveals that the mechanism of mouse IRF-3 activation is similar but distinct from human IRF-3. These structural and functional studies reveal the detailed mechanism of IRF-3 activation upon phosphorylation.","journal":"The Journal of Immunology","year":2020,"id":64034,"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":39,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":265655,"name":"Baoyu Zhao","orcid":null,"position":1,"is_corresponding":false},{"id":338916,"name":"Pengbiao Xu","orcid":"0000-0003-0098-8875","position":2,"is_corresponding":false},{"id":340632,"name":"Xinsheng Gao","orcid":null,"position":3,"is_corresponding":false},{"id":338917,"name":"Lei Chi","orcid":"0000-0002-7824-2785","position":4,"is_corresponding":false},{"id":338918,"name":"Huajun Han","orcid":"0000-0001-5381-1956","position":5,"is_corresponding":false},{"id":249510,"name":"Banumathi Sankaran","orcid":"0000-0002-3266-8131","position":6,"is_corresponding":false},{"id":264702,"name":"Pingwei Li","orcid":"0000-0002-1815-3107","position":7,"is_corresponding":false},{"id":338915,"name":"Tao Jing","orcid":"0000-0003-1936-4392","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T21:12:32.635050Z","pmid":"32826280","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":[]}