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(ISCIII)","award":["PID-2021-123810OB-I00"],"award-info":[{"award-number":["PID-2021-123810OB-I00"]}]},{"name":"FEDER Funding Program from the European Union and by Instituto de Salud Carlos III (ISCIII)","award":["CNS2022-135276"],"award-info":[{"award-number":["CNS2022-135276"]}]},{"name":"FEDER Funding Program from the European Union and by Instituto de Salud Carlos III (ISCIII)","award":["2021-050-INTRAMURAL NOV-SAALM"],"award-info":[{"award-number":["2021-050-INTRAMURAL NOV-SAALM"]}]},{"name":"FEDER Funding Program from the European Union and by Instituto de Salud Carlos III (ISCIII)","award":["Grant IDE\/2024\/000775"],"award-info":[{"award-number":["Grant IDE\/2024\/000775"]}]},{"name":"FEDER Funding Program from the European Union and by Instituto de Salud Carlos III (ISCIII)","award":["PI22\/00738"],"award-info":[{"award-number":["PI22\/00738"]}]},{"name":"FEDER Funding Program from the European Union and by Instituto de Salud Carlos III (ISCIII)","award":["PI23\/00567"],"award-info":[{"award-number":["PI23\/00567"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>CD9 protein belongs to a family of proteins called tetraspanins, so named for their four-transmembrane-spanning architectures. These proteins are located in domains in the plasmatic membrane, called tetraspanin-enriched microdomains (TEMs). Several proteases and cellular receptors for virus entry cluster into TEMs, suggesting that TEMs are preferred virus entry portals. Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates virus attachment and entry into cells by binding to human angiotensin-converting enzyme 2 (ACE-2). In addition, the secretory, type-I membrane-bound SARS-CoV-2 S protein is synthesized as a precursor (proS) that undergoes posttranslational cleavages by host cell proteases, such as furin and TMPRSS2. Moreover, it has been shown that neuropilin-1 (NRP1), which is known to bind furin-cleaved substrates, potentiates SARS-CoV-2 infectivity. Our results indicate that CD9 facilitates SARS-CoV-2 infection. In addition, we show how knocking out CD9 leads to a decrease in the expression of NRP1, a protein that improves SARS-CoV-2 infection. Furthermore, we show that CD9 colocalizes with ACE-2, NRP1, furin, and TMPRSS2 at the plasma membrane; that the absence of CD9 decreases the expression of these proteins on the plasma membrane CD9-enriched microdomains, and that CD9 interacts with ACE2. In conclusion, our data suggest that CD9 facilitates SARS-CoV-2 infection and that CD9 brings together different host proteins involved in SARS-CoV-2 attachment and entry into host cells, such as ACE2, NRP1, furin, and TMPRSS2. Importantly, the fact that a blocking antibody targeting CD9 can effectively reduce SARS-CoV-2 titers highlights not only the mechanistic role of CD9 in viral entry but also offers translational potential, suggesting that tetraspanin-targeting antibodies could be developed as therapeutic agents against SARS-CoV-2 and possibly other coronaviruses, with meaningful implications for clinical intervention.<\/jats:p>","DOI":"10.3390\/v17081141","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T13:18:14Z","timestamp":1755695894000},"page":"1141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Tetraspanin CD9 Facilitates SARS-CoV-2 Infection and Brings Together Different Host Proteins Involved in SARS-CoV-2 Attachment and Entry into Host Cells"],"prefix":"10.3390","volume":"17","author":[{"given":"Vanessa","family":"Rivero","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, Centro Nacional de Biotecnolog\u00eda-Consejo Superior de Investigaciones Cient\u00edficas (CNB-CSIC), 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3966-212X","authenticated-orcid":false,"given":"Mar\u00eda Laura","family":"Saiz","sequence":"additional","affiliation":[{"name":"Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Kidney Disease Research Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7970-1277","authenticated-orcid":false,"given":"Daniel","family":"Torralba","sequence":"additional","affiliation":[{"name":"PharmaMar S.A., Colmenar Viejo, 28770 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"L\u00f3pez-Larrea","sequence":"additional","affiliation":[{"name":"Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Kidney Disease Research Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3431-4206","authenticated-orcid":false,"given":"Beatriz","family":"Suarez-Alvarez","sequence":"additional","affiliation":[{"name":"Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Kidney Disease Research Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7888-7372","authenticated-orcid":false,"given":"Marta L.","family":"DeDiego","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, Centro Nacional de Biotecnolog\u00eda-Consejo Superior de Investigaciones Cient\u00edficas (CNB-CSIC), 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41586-020-2180-5","article-title":"Structure of the SARS-CoV-2 Spike Receptor-Binding Domain Bound to the ACE2 Receptor","volume":"581","author":"Lan","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/s41564-020-0688-y","article-title":"Functional Assessment of Cell Entry and Receptor Usage for SARS-CoV-2 and Other Lineage B Betacoronaviruses","volume":"5","author":"Letko","year":"2020","journal-title":"Nat. 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