{"doi":"10.1126/science.adf6249","title":"Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras","abstract":"Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells. We found that disrupting retromer genes improved target degradation by reducing LYTAC recycling to the plasma membrane. Neddylated cullin-3 facilitated LYTAC-complex lysosomal maturation and was a predictive marker for LYTAC efficacy. A substantial fraction of cell surface CI-M6PR remains occupied by endogenous M6P-modified glycoproteins. Thus, inhibition of M6P biosynthesis increased the internalization of LYTAC-target complexes. Our findings inform design strategies for next-generation LYTACs and elucidate aspects of cell surface receptor occupancy and trafficking.","journal":"Science","year":2023,"id":315416,"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":166,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":218283,"name":"Nicholas M. Riley","orcid":"0000-0002-1536-2966","position":1,"is_corresponding":false},{"id":830263,"name":"Roarke A. Kamber","orcid":"0000-0001-8462-4782","position":2,"is_corresponding":false},{"id":218281,"name":"Simon Wisnovsky","orcid":"0000-0003-4010-4309","position":3,"is_corresponding":false},{"id":1016565,"name":"S. Hase","orcid":"0009-0009-5056-8853","position":4,"is_corresponding":false},{"id":62612,"name":"Michael C. Bassik","orcid":"0000-0001-5185-8427","position":5,"is_corresponding":false},{"id":218279,"name":"Steven M. Banik","orcid":"0000-0002-0544-6488","position":6,"is_corresponding":false},{"id":218284,"name":"Carolyn R. Bertozzi","orcid":"0000-0003-4482-2754","position":7,"is_corresponding":false},{"id":218282,"name":"Green Ahn","orcid":"0000-0003-3086-4849","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T01:06:25.560098Z","pmid":"37856615","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":[]}