{"doi":"10.1016/j.jbc.2021.101072","title":"Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1)","abstract":"Multifunctionality of tissue inhibitor of metalloproteinases-1 (TIMP-1) comprising antiproteolytic as well as cytokinic activity has been attributed to its N-terminal and C-terminal domains, respectively. The molecular basis of the emerging proinflammatory cytokinic activity of TIMP-1 is still not completely understood. The cytokine receptor invariant chain (CD74) is involved in many inflammation-associated diseases and is highly expressed by immune cells. CD74 triggers zeta chain-associated protein kinase-70 (ZAP-70) signaling-associated activation upon interaction with its only known ligand, the macrophage migration inhibitory factor. Here, we demonstrate TIMP-1-CD74 interaction by coimmunoprecipitation and confocal microscopy in cells engineered to overexpress CD74. In silico docking in HADDOCK predicted regions of the N-terminal domain of TIMP-1 (N-TIMP-1) to interact with CD74. This was experimentally confirmed by confocal microscopy demonstrating that recombinant N-TIMP-1 lacking the entire C-terminal domain was sufficient to bind CD74. Interaction of TIMP-1 with endogenously expressed CD74 was demonstrated in the Namalwa B lymphoma cell line by dot blot binding assays as well as confocal microscopy. Functionally, we demonstrated that TIMP-1-CD74 interaction triggered intracellular ZAP-70 activation. N-TIMP-1 was sufficient to induce ZAP-70 activation and interference with the cytokine-binding site of CD74 using a synthetic peptide-abrogated TIMP-1-mediated ZAP-70 activation. Altogether, we here identified CD74 as a receptor and mediator of cytokinic TIMP-1 activity and revealed TIMP-1 as moonlighting protein harboring both cytokinic and antiproteolytic activity within its N-terminal domain. Recognition of this functional TIMP-1-CD74 interaction may shed new light on clinical attempts to therapeutically target ligand-induced CD74 activity in cancer and other inflammatory diseases.","journal":"Journal of Biological Chemistry","year":2021,"id":173653,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":711642,"name":"Celina Eckfeld","orcid":"0000-0002-2807-5368","position":1,"is_corresponding":false},{"id":712381,"name":"Laura Flüter","orcid":null,"position":2,"is_corresponding":false},{"id":711643,"name":"Selina J. Keppler","orcid":"0000-0002-9010-8044","position":3,"is_corresponding":false},{"id":711644,"name":"Ritu Mishra","orcid":"0000-0002-3581-5918","position":4,"is_corresponding":false},{"id":561,"name":"Percy A. Knolle","orcid":"0000-0003-2983-0414","position":5,"is_corresponding":false},{"id":374626,"name":"Felix Bayerl","orcid":"0000-0002-4737-1808","position":6,"is_corresponding":false},{"id":711645,"name":"Jan P. Böttcher","orcid":"0000-0002-8163-8107","position":7,"is_corresponding":false},{"id":711646,"name":"Chris D. Hermann","orcid":"0000-0002-2269-5259","position":8,"is_corresponding":false},{"id":711647,"name":"Daniel Häußler","orcid":"0000-0003-0658-3262","position":9,"is_corresponding":false},{"id":711648,"name":"Achim Krüger","orcid":"0000-0002-1517-9256","position":10,"is_corresponding":false},{"id":711641,"name":"Benjamin Schoeps","orcid":"0000-0003-3934-0849","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-18T23:46:49.903770Z","pmid":"34391782","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":[]}