{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:03:34Z","timestamp":1787022214202,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013659","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000}}],"reference-count":107,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI181742"],"award-info":[{"award-number":["R21AI181742"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI129269"],"award-info":[{"award-number":["R01AI129269"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI136581 and R01AI162633"],"award-info":[{"award-number":["R01AI136581 and R01AI162633"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI189220, R33AI169659, and P30CA086862"],"award-info":[{"award-number":["R01AI189220, R33AI169659, and P30CA086862"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) restricts a broad spectrum of viruses through multifaceted mechanisms. It also limits spontaneous- and virus-induced innate immune responses by suppressing proinflammatory cytokine and type-I interferon (IFN-I) production. Some viruses escape SAMHD1 restriction and utilize SAMHD1-mediated innate immune suppression to establish effective infection through IFN antagonism. Our previous studies showed that SAMHD1 is a proviral factor facilitating replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in human macrophages, monocytic THP-1 and epithelial-like HEK293T cell lines by suppressing IFN responses. However, it is unclear about the function of SAMHD1 in lung epithelial cells during SARS-CoV-2 infection. Here, we report that SAMHD1 knockout (KO) restricts SARS-CoV-2 replication in lung epithelial Calu-3 cells by suppressing endogenous expression of the viral receptor angiotensin-converting enzyme 2 (ACE2) via hepatocyte nuclear factor 1-alpha (HNF1\u03b1) and HNF1\u03b2. Using pseudotyped SARS-CoV-2 and lentiviral vectors, we found that SARS-CoV-2 spike protein-mediated viral entry was suppressed in SAMHD1 KO Calu-3 cells. SAMHD1 KO repressed ACE2 expression in Calu-3 cells at mRNA and protein levels. Functional analyses revealed that HNF1\u03b1 and HNF1\u03b2 were crucial for the endogenous ACE2 expression in Calu-3 cells. Additionally, SAMHD1 KO led to a reduction in the expression levels and ACE2-promoting function of HNF1\u03b1 and HNF1\u03b2. Inhibition of IFN antiviral response by baricitinib, a Janus kinase 1 and 2 (JAK 1\/2) inhibitor, did not revert the suppression of SARS-CoV-2 in SAMHD1 KO Calu-3 cells. SAMHD1 knock-in and deoxynucleoside supplementation experiments indicated that SAMHD1 expression and dNTP pool balance collectively regulated HNF1-mediated ACE2 expression in Calu-3 cells. Our findings demonstrate that SAMHD1 depletion hinders HNF1-mediated ACE2 expression and SARS-CoV-2 replication in Calu-3 cells via a novel mechanism beyond its IFN-suppressive function.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013659","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T17:31:41Z","timestamp":1773941501000},"page":"e1013659","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["SAMHD1 depletion restricts SARS-CoV-2 infection by suppressing HNF1-dependent ACE2 expression in lung epithelial cells"],"prefix":"10.1371","volume":"22","author":[{"given":"Pak-Hin Hinson","family":"Cheung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pearl","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Ambrus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shravya","family":"Honne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baek","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5468-2487","authenticated-orcid":true,"given":"Li","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"issue":"7353","key":"ppat.1013659.ref001","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/nature10195","article-title":"Vpx 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