{"doi":"10.1016/j.jbc.2024.107284","title":"A proteomics-based survey reveals thrombospondin-4 as a ligand regulated by the mannose receptor in the injured lung","abstract":"Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. WT and MR-deficient mice were exposed to lipopolysaccharide, after which the protein content in their lung epithelial lining fluid was compared by tandem mass tag-based mass spectrometry. More than 1200 proteins were identified in the epithelial lining fluid using this unbiased approach, but only six showed a statistically different abundance. Among these, an unexpected potential new ligand, thrombospondin-4 (TSP-4), displayed a striking 17-fold increased abundance in the MR-deficient mice. Experiments using exogenous addition of TSP-4 to MR-transfected CHO cells or MR-positive alveolar macrophages confirmed that TSP-4 is a ligand for MR-dependent endocytosis. Similar studies revealed that the molecular interaction with TSP-4 depends on both the lectin activity and the fibronectin type-II domain of MR and that a closely related member of the TSP family, TSP-5, is also efficiently internalized by the receptor. This was unlike the other members of this protein family, including TSPs -1 and -2, which are ligands for a close MR homologue known as urokinase plasminogen activator receptor-associated protein. Our study shows that MR takes part in the regulation of TSP-4, an important inflammatory component in the injured lung, and that two closely related endocytic receptors, expressed on different cell types, undertake the selective endocytosis of distinct members of the TSP family.","journal":"Journal of Biological Chemistry","year":2024,"id":473252,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"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":507011,"name":"Henrik J. Jürgensen","orcid":"0000-0003-4405-2307","position":1,"is_corresponding":false},{"id":1309339,"name":"Signe S. Heltberg","orcid":null,"position":2,"is_corresponding":false},{"id":507007,"name":"Henrik Gårdsvoll","orcid":"0000-0003-0691-3567","position":3,"is_corresponding":false},{"id":371359,"name":"Thomas Bugge","orcid":"0000-0001-7046-4060","position":4,"is_corresponding":false},{"id":394,"name":"Erwin M. Schoof","orcid":"0000-0002-3117-7832","position":5,"is_corresponding":false},{"id":507013,"name":"Lars H. Engelholm","orcid":"0000-0002-6616-1232","position":6,"is_corresponding":false},{"id":507014,"name":"Niels Behrendt","orcid":"0000-0003-1833-3922","position":7,"is_corresponding":false},{"id":507008,"name":"Kirstine Sandal Nørregaard","orcid":"0000-0002-1299-0991","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:06:01.000126Z","pmid":"38614208","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":[]}