{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:45:24Z","timestamp":1790379924424,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Abdullah International Medical Research Center (KAIMRC)","award":["RA20\/017-A"],"award-info":[{"award-number":["RA20\/017-A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. Methods: Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo\u00ae luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. Results: TUN (5 \u00b5g\/mL) and THA (1 \u00b5M) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA\u2019s attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78\/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2\u03b1-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. Conclusions: These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.<\/jats:p>","DOI":"10.3390\/cells13090769","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T08:42:57Z","timestamp":1714639377000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-4269","authenticated-orcid":false,"given":"Abeer","family":"Al Otaibi","sequence":"first","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia"},{"name":"Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia"},{"name":"King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindiyan","family":"Al Shaikh Mubarak","sequence":"additional","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia"},{"name":"Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia"},{"name":"King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatimah","family":"Al Hejji","sequence":"additional","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi 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Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia"},{"name":"King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2413-6637","authenticated-orcid":false,"given":"Ali","family":"Al Qarni","sequence":"additional","affiliation":[{"name":"King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia"},{"name":"Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia"},{"name":"King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6049-3383","authenticated-orcid":false,"given":"Naif Khalaf Al","family":"Harbi","sequence":"additional","affiliation":[{"name":"Vaccine Development Unit, 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