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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells using angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as viral receptor and priming protease during the viral entry phase. Here, we report that TMPRSS2 reduces the infectivity of SARS-CoV-2 and HIV-1 during the viral production phase. Treatment of virus-producing cells with a TMPRSS2 inhibitor increases the production of infectious virions. TMPRSS2 enzymatic activity specifically disrupts the trans-Golgi by phosphorylating Golgi stacking proteins through ERK activation, which disturbs virion spike incorporation and structural maturation of the viral envelope glycoproteins, causing lower viral infectivity. We find that SARS-CoV-2 envelope protein (E protein) counteracts this TMPRSS2 activity to rescue SARS-CoV-2-S incorporation. These results demonstrate negative regulation of viral envelope glycoprotein incorporation by TMPRSS2 and reveal that SARS-CoV-2 regulates the Golgi system to create an optimal viral replication environment.<\/jats:p>","DOI":"10.1038\/s44319-026-00797-2","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T09:03:21Z","timestamp":1779181401000},"page":"3424-3453","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TMPRSS2-induced Golgi disruption restricts the incorporation of virus envelope glycoproteins into virions"],"prefix":"10.1038","volume":"27","author":[{"given":"Sayuri","family":"Seki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeyoshi","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Sugimoto-Ishige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Unno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machie","family":"Sakuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4456-7274","authenticated-orcid":false,"given":"Shinsuke","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aki","family":"Tanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieko","family":"Makino-Okamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sewon","family":"Ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehiro","family":"Fukuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7552-179X","authenticated-orcid":false,"given":"Michishige","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Tsumagari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7451-4982","authenticated-orcid":false,"given":"Koshi","family":"Imami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-3547","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Kubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3820-9542","authenticated-orcid":false,"given":"Tadaki","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-5854","authenticated-orcid":false,"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Matano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2349-6665","authenticated-orcid":false,"given":"Kosuke","family":"Miyauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"797_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.957224","volume":"13","author":"C Agostinis","year":"2022","unstructured":"Agostinis C, Toffoli M, Spazzapan M, Balduit A, Zito G, Mangogna A, Zupin L, Salviato T, Maiocchi S, Romano F et al (2022) SARS-CoV-2 modulates virus receptor expression in placenta and can induce trophoblast fusion, inflammation and endothelial permeability. 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