{"doi":"10.3389/fimmu.2020.550824","title":"β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4","abstract":"The chemokine receptor CXCR4 plays a fundamental role in homeostasis and pathology by orchestrating recruitment and positioning of immune cells, under the guidance of a CXCL12 gradient. The ability of chemokines to form heterocomplexes, enhancing their function, represents an additional level of regulation on their cognate receptors. In particular, the multi-faceted activity of the heterocomplex formed between CXCL12 and the alarmin HMGB1 is emerging as an unexpected player able to modulate a variety of cell responses, spanning from tissue regeneration to chronic inflammation. Nowadays, little is known on the selective signaling pathways activated when CXCR4 is triggered by the CXCL12/HMGB1 heterocomplex. In the present work, we demonstrate that this heterocomplex acts as a CXCR4 balanced agonist, activating both G protein and β-arrestins-mediated signaling pathways to sustain chemotaxis. We generated β-arrestins knock out HeLa cells by CRISPR/Cas9 technology and show that the CXCL12/HMGB1 heterocomplex-mediated actin polymerization is primarily β-arrestin1 dependent, while chemotaxis requires both β-arrestin1 and β-arrestin2. Triggering of CXCR4 with the CXCL12/HMGB1 heterocomplex leads to an unexpected receptor retention on the cell surface, which depends on β-arrestin2. In conclusion, the CXCL12/HMGB1 heterocomplex engages the β-arrestin proteins differently from CXCL12, promoting a prompt availability of CXCR4 on the cell surface, and enhancing directional cell migration. These data unveil the signaling induced by the CXCL12/HMGB1 heterocomplex in view of identifying biased CXCR4 antagonists or agonists targeting the variety of functions it exerts.","journal":"Frontiers in Immunology","year":2020,"id":94958,"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":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":338381,"name":"Marc Artinger","orcid":null,"position":1,"is_corresponding":false},{"id":472669,"name":"Massimo Locati","orcid":"0000-0003-3077-590X","position":2,"is_corresponding":false},{"id":472670,"name":"Laurent Perez","orcid":"0000-0002-8860-7928","position":3,"is_corresponding":false},{"id":337014,"name":"Daniel F. Legler","orcid":"0000-0001-8610-4764","position":4,"is_corresponding":false},{"id":472671,"name":"Marco E. Bianchi","orcid":"0000-0002-5329-6445","position":5,"is_corresponding":false},{"id":351855,"name":"Curzio Rüegg","orcid":"0000-0001-9137-7695","position":6,"is_corresponding":false},{"id":472672,"name":"Marcus Thelen","orcid":"0000-0002-3443-1605","position":7,"is_corresponding":false},{"id":370582,"name":"Adriano Marchese","orcid":null,"position":8,"is_corresponding":false},{"id":355190,"name":"Marco Rocchi","orcid":"0000-0002-0056-5795","position":9,"is_corresponding":false},{"id":472673,"name":"Valentina Cecchinato","orcid":"0000-0001-7415-8706","position":10,"is_corresponding":false},{"id":472674,"name":"Mariagrazia Uguccioni","orcid":"0000-0002-9570-7011","position":11,"is_corresponding":false},{"id":472668,"name":"Gianluca D’Agostino","orcid":"0000-0002-7346-9278","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T22:33:30.364261Z","pmid":"33072091","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":[]}