{"doi":"10.1111/febs.17222","title":"<scp>TRAF2</scp> associates with cullin neddylation complex assembly","abstract":"<jats:p>Cullin‐based RING ligases (CRLs) comprise the largest family of ubiquitin E3 ligases. CRL activity is tightly regulated by cullin neddylation, which has been associated with various diseases. Although inhibitors of CRLs neddylation have been reported, there is a lack of small molecules that can selectively target individual cullins. Here, we identified a natural product, liquidambaric acid (LDA), with relatively selective inhibition properties against cullin (Cul) 2 neddylation, and found that its target, Tumor Necrosis Factor receptor‐associated factor 2 (TRAF2) was required for the activity. TRAF2 associates with the Cul2 neddylation complex and regulates the machinery assembly, especially that of E2 (UBC12) and E3 (RBX1) enzymes. In addition, we demonstrated that by intervention of the associations between TRAF2 and the neddylation machinery, LDA disturbed NEDD8 transfer from E1 to E2, therefore blocking Cul2 neddylation. Taken together, we show that TRAF2 plays a positive role in neddylation cascades, and we have identified a small molecule capable of selective modulation of cullin neddylation.</jats:p>","journal":"The FEBS Journal","year":2024,"id":593868,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"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":407255,"name":"Qi Zhang","orcid":"0000-0002-5203-8778","position":1,"is_corresponding":false},{"id":164907,"name":"Yu Xu","orcid":null,"position":2,"is_corresponding":false},{"id":1395160,"name":"Rong Yan","orcid":"0009-0009-8267-9793","position":3,"is_corresponding":false},{"id":1237509,"name":"Yuting Pan","orcid":"0009-0002-0920-5865","position":4,"is_corresponding":false},{"id":1520006,"name":"Ying Xuan","orcid":null,"position":5,"is_corresponding":false},{"id":1520007,"name":"Mengzhen Shen","orcid":null,"position":6,"is_corresponding":false},{"id":1520008,"name":"Xianzhi Chen","orcid":null,"position":7,"is_corresponding":false},{"id":377084,"name":"Hongyan Zhu","orcid":"0000-0002-5985-8533","position":8,"is_corresponding":false},{"id":1520009,"name":"Xisong Ke","orcid":"0000-0001-7328-7354","position":9,"is_corresponding":false},{"id":366980,"name":"Yi Qu","orcid":"0000-0002-1420-7753","position":10,"is_corresponding":false},{"id":474983,"name":"Xue Zhang","orcid":"0000-0002-1243-475X","position":11,"is_corresponding":false},{"id":1340465,"name":"Tiantian Wang","orcid":"0000-0003-2769-6418","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<scp>TRAF2</scp> associates with cullin neddylation complex assembly","abstract":"<jats:p>Cullin‐based RING ligases (CRLs) comprise the largest family of ubiquitin E3 ligases. CRL activity is tightly regulated by cullin neddylation, which has been associated with various diseases. Although inhibitors of CRLs neddylation have been reported, there is a lack of small molecules that can selectively target individual cullins. Here, we identified a natural product, liquidambaric acid (LDA), with relatively selective inhibition properties against cullin (Cul) 2 neddylation, and found that its target, Tumor Necrosis Factor receptor‐associated factor 2 (TRAF2) was required for the activity. TRAF2 associates with the Cul2 neddylation complex and regulates the machinery assembly, especially that of E2 (UBC12) and E3 (RBX1) enzymes. In addition, we demonstrated that by intervention of the associations between TRAF2 and the neddylation machinery, LDA disturbed NEDD8 transfer from E1 to E2, therefore blocking Cul2 neddylation. Taken together, we show that TRAF2 plays a positive role in neddylation cascades, and we have identified a small molecule capable of selective modulation of cullin neddylation.</jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38978293","pmcid":null,"openalex_id":"https://openalex.org/W4400474006","authors":[],"funders":[{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2021‐01‐07‐00‐10‐E00116","title":null},{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2023‐01‐07‐00‐10‐E00046","title":null},{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2023ZKZD49","title":null},{"funder_name":"Science and Technology Commission of Shanghai Municipality","grant_id":"21S11900900","title":null},{"funder_name":"Science and Technology Commission of Shanghai Municipality","grant_id":"22XD1403200","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81874210","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82173845","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82204430","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82274147","title":null},{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2021-01-07-00-10-E00116","title":null},{"funder_name":"Shanghai Municipal Education Commission","grant_id":"2023-01-07-00-10-E00046","title":null}],"total_grants":11,"fwci":0.5598,"citation_percentile":0.65203003,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/febs.17222","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/febs.17222","host_type":"publisher"},{"url":"https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.17222","host_type":"publisher"},{"url":"https://doi.org/10.1111/febs.17222","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38978293","host_type":"repository"}],"fields_of_study":["Ubiquitin and proteasome pathways","Autophagy in Disease and Therapy","Toxoplasma gondii Research Studies","Cullin Proteins","Humans","NEDD8 Protein","TNF Receptor-Associated Factor 2","Ubiquitin-Conjugating Enzymes","HEK293 Cells","Ubiquitins","Carrier Proteins"],"mesh_terms":["NEDD8 Protein","Carrier Proteins","Humans","Ubiquitins","Ubiquitin-Conjugating Enzymes","Cullin Proteins","TNF Receptor-Associated Factor 2","HEK293 Cells"],"keywords":["Neddylation","Cullin","NEDD8","Ubiquitin","Cell biology","Biology","Biochemistry","Ubiquitin ligase","TRAF2","Cul2","Liquidambaric Acid"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T12:34:59.901555Z","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":[]}