{"doi":"10.1021/jacs.5c14363","title":"Unbiased RNA Degrader Identification Uncovers an LC3B-Recruiting Chimera for <i>COL15A1</i> mRNA Degradation","abstract":"High Resolution Image Download MS PowerPoint Slide Heterobifunctional RNA degraders, such as ribonuclease-targeting chimeras (RiboTACs), eliminate structured RNAs by recruiting endogenous effector proteins. Here, we expand the effector toolbox by co-opting microtubule-associated protein 1 light chain 3B (MAP1LC3B, also known as LC3B), a core autophagy component recently implicated in mRNA decay. An RNA-binding fragment ( F1 ) with a mapped transcriptome-wide binding profile was conjugated to the LC3B ligand ispinesib to generate the degrader F1-ispinesib . Integration of RNA-seq and Chemical Cross-Linking and Isolation by Pull-down combined with NGS Sequencing (Chem-CLIP-seq) data identified collagen type XV alpha 1 chain ( COL15A1 ) mRNA as a target selectively degraded by F1-Ispinesib . The induced COL15A1 mRNA decay was LC3B- and autophagy-dependent, confirmed by genetic and pharmacological inhibition. Cellular engagement of LC3B was validated by NanoBRET and photocatalytic proximity labeling. In human aortic smooth muscle cells, F1-ispinesib phenocopied siRNA-mediated COL15A1 knockdown, reducing protein levels, suppressing proliferation, and enhancing migration. A synthetic LC3B recruitment model also recapitulated the on-target COL15A1 mRNA decay, further supporting the degradation mechanism. These findings establish LC3B as a recruitable effector protein for small-molecule-directed RNA decay and provide a general URID framework for discovering degraders that harness diverse RNA-regulatory proteins.","journal":"Journal of the American Chemical Society","year":2025,"id":548996,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"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":645000,"name":"Yuquan Tong","orcid":"0000-0003-0793-7747","position":1,"is_corresponding":false},{"id":804221,"name":"Patrick R. A. Zanon","orcid":"0000-0002-8883-8275","position":2,"is_corresponding":false},{"id":1377185,"name":"Jielei Wang","orcid":"0009-0007-0072-039X","position":3,"is_corresponding":false},{"id":1442675,"name":"Toru Tanaka","orcid":"0000-0003-2555-7318","position":4,"is_corresponding":false},{"id":249554,"name":"Jessica L. Childs‐Disney","orcid":"0009-0001-7829-3240","position":5,"is_corresponding":false},{"id":249561,"name":"Matthew D. Disney","orcid":"0000-0001-8486-1796","position":6,"is_corresponding":false},{"id":860630,"name":"Xun‐Cheng Su","orcid":"0000-0003-3051-0047","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:03.053965Z","pmid":"41297909","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":[]}