{"doi":"10.1093/nar/gkae161","title":"WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination","abstract":"Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two structurally similar substrate-recognizing components of Cullin-RING E3 ligases, WSB1 and WSB2, can recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. We showed that WSB1/2 negatively regulated a subset of NF-κB target genes via associating with chromatin where they targeted methylated RelA for ubiquitination, facilitating the termination of NF-κB-dependent transcription. WSB1/2 specifically interacted with methylated lysines (K) 314 and 315 of RelA via their N-terminal WD-40 repeat (WDR) domains, thereby promoting ubiquitination of RelA. Computational modeling further revealed that a conserved aspartic acid (D) at position 158 within the WDR domain of WSB2 coordinates K314/K315 of RelA, with a higher affinity when either of the lysines is methylated. Mutation of D158 abolished WSB2's ability to bind to and promote ubiquitination of methylated RelA. Together, our study identifies a novel function and the underlying mechanism for WSB1/2 in degrading chromatin-bound methylated RelA and preventing sustained NF-κB activation, providing potential new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.","journal":"Nucleic Acids Research","year":2024,"id":437952,"datarank":0.4737363501952545,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.11405205927549882,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.11405205927549882,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":9,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9469,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE233286"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":814175,"name":"Yuanyuan Yu","orcid":"0000-0002-5379-5148","position":1,"is_corresponding":false},{"id":1247818,"name":"Xiuqun Zou","orcid":null,"position":2,"is_corresponding":false},{"id":1247424,"name":"Yaning Du","orcid":"0009-0000-1751-9392","position":3,"is_corresponding":false},{"id":1247819,"name":"Qiankun Liang","orcid":null,"position":4,"is_corresponding":false},{"id":1247425,"name":"Mengyao Gong","orcid":"0009-0004-0950-5985","position":5,"is_corresponding":false},{"id":1247426,"name":"Yurong He","orcid":"0009-0004-5692-7996","position":6,"is_corresponding":false},{"id":1247820,"name":"Junqi Luo","orcid":null,"position":7,"is_corresponding":false},{"id":1247427,"name":"Dandan Wu","orcid":"0000-0002-0453-008X","position":8,"is_corresponding":false},{"id":1247428,"name":"Xiaoli Jiang","orcid":"0000-0003-4628-3256","position":9,"is_corresponding":false},{"id":1043289,"name":"Matt Sinclair","orcid":"0000-0001-9206-1895","position":10,"is_corresponding":false},{"id":98027,"name":"Emad Tajkhorshid","orcid":"0000-0001-8434-1010","position":11,"is_corresponding":false},{"id":312599,"name":"Hongzhuan Chen","orcid":"0000-0002-5367-2949","position":12,"is_corresponding":false},{"id":1247429,"name":"Zhaoyuan Hou","orcid":"0000-0003-0634-2020","position":13,"is_corresponding":false},{"id":461067,"name":"Yuejuan Zheng","orcid":"0000-0001-9995-4960","position":14,"is_corresponding":false},{"id":487157,"name":"Lin‐Feng Chen","orcid":"0000-0003-1809-1580","position":15,"is_corresponding":false},{"id":488247,"name":"Xiaodong Yang","orcid":"0000-0001-6895-0713","position":16,"is_corresponding":false},{"id":638951,"name":"Jie Zhang","orcid":"0000-0001-6795-8000","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T02:00:34.490087Z","pmid":"38452206","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":[]}