{"doi":"10.1073/pnas.2311913120","title":"Integrin α <sub>5</sub> β <sub>1</sub> contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction","abstract":"The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infects host cells by engaging its spike (S) protein with human ACE2 receptor. Recent studies suggest the involvement of integrins in SARS-CoV-2 infection through interaction with the S protein, but the underlying mechanism is not well understood. This study investigated the role of integrin α 5 β 1 , which recognizes the Arg-Gly-Asp (RGD) motif in its physiological ligands, in S-mediated virus entry and cell–cell fusion. Our results showed that α 5 β 1 does not directly contribute to S-mediated cell entry, but it enhances S-mediated cell–cell fusion in collaboration with ACE2. This effect cannot be inhibited by the putative α 5 β 1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α 5 cytoplasmic tail (CT). We detected a direct interaction between α 5 β 1 and the S protein, but this interaction does not rely on the RGD-containing receptor binding domain of the S1 subunit of the S protein. Instead, it involves the S2 subunit of the S protein and α 5 β 1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-κB activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1β. These effects can be attenuated by the loss of α 5 expression or inhibition of the α 5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α 5 CT and PDE4D pathway. These findings provide molecular insights into the pathogenesis of SARS-CoV-2 mediated by a nonclassical RGD-independent ligand-binding and signaling function of integrin α 5 β 1 and suggest potential targets for antiviral treatment.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":329579,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"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":785566,"name":"Zhengli Wang","orcid":"0000-0003-4268-9195","position":1,"is_corresponding":false},{"id":1053299,"name":"Huong T. T. Nguyen","orcid":null,"position":2,"is_corresponding":false},{"id":1053300,"name":"Abigail J. Watson","orcid":null,"position":3,"is_corresponding":false},{"id":957316,"name":"Qifang Lao","orcid":null,"position":4,"is_corresponding":false},{"id":707767,"name":"An Li","orcid":"0000-0002-8476-8783","position":5,"is_corresponding":false},{"id":785567,"name":"Jieqing Zhu","orcid":"0000-0003-4508-4263","position":6,"is_corresponding":false},{"id":956837,"name":"Heng Zhang","orcid":"0000-0002-6580-2464","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:05.843139Z","pmid":"38060559","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":[]}