{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:26:01Z","timestamp":1784258761391,"version":"3.55.0"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019270","name":"Shimizu Foundation for Immunology and Neuroscience","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019270","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kao Research Council for the Study of Healthcare Science"},{"DOI":"10.13039\/100019432","name":"Fujiwara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019432","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06016"],"award-info":[{"award-number":["21K06016"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LiMe Office of Director's Research Grants Program"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection suppresses host innate immunity and impairs cell viability. Among the viral proteins, ORF6 exhibits potent interferon (IFN) antagonistic activity and cellular toxicity. It also interacts with the RNA export factor RAE1, which bridges the nuclear pore complex and nuclear export receptors, suggesting an effect on RNA export. Using the <jats:italic>Xenopus<\/jats:italic> oocyte microinjection system, I found that ORF6 blocked the export of not only mRNA but also spliceosomal U snRNA. I further demonstrated that ORF6 affects the interaction between RAE1 and nuclear export receptors and inhibits the RNA binding of RAE1. These effects of ORF6 may cumulatively block the export of several classes of RNA. I also found that ORF6 binds RNA and forms oligomers. These findings provide insights into the suppression of innate immune responses and the reduction in cell viability caused by SARS-CoV-2 infection, contributing to the development of antiviral drugs targeting ORF6.<\/jats:p>","DOI":"10.1371\/journal.pone.0312098","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T17:39:38Z","timestamp":1730396378000},"page":"e0312098","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["The SARS-CoV-2 ORF6 protein inhibits nuclear export of mRNA and spliceosomal U 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Gadal","year":"2001","journal-title":"Mol Cell Biol"},{"issue":"5","key":"pone.0312098.ref018","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1083\/jcb.151.5.1057","article-title":"Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit","volume":"151","author":"JH Ho","year":"2000","journal-title":"J Cell Biol"},{"issue":"6","key":"pone.0312098.ref019","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/S0092-8674(00)80371-2","article-title":"CRM1 is an export receptor for leucine-rich nuclear export signals","volume":"90","author":"M Fornerod","year":"1997","journal-title":"Cell"},{"issue":"2","key":"pone.0312098.ref020","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1534\/genetics.106.062117","article-title":"Ltv1 is required for efficient nuclear export of the ribosomal small subunit in Saccharomyces cerevisiae","volume":"174","author":"RM 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that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains","volume":"145","author":"CE Pritchard","year":"1999","journal-title":"J Cell Biol"},{"issue":"2","key":"pone.0312098.ref034","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1083\/jcb.136.2.241","article-title":"The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways","volume":"136","author":"MA Powers","year":"1997","journal-title":"J Cell Biol"},{"issue":"2","key":"pone.0312098.ref035","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/15216540500078608","article-title":"Viral interactions with the nuclear transport machinery: discovering and disrupting pathways","volume":"57","author":"BM Fontoura","year":"2005","journal-title":"IUBMB Life"},{"issue":"5","key":"pone.0312098.ref036","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/S1097-2765(00)00120-9","article-title":"Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98","volume":"6","author":"C null von Kobbe","year":"2000","journal-title":"Mol Cell"},{"issue":"1","key":"pone.0312098.ref037","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.molcel.2004.11.023","article-title":"VSV disrupts the Rae1\/mrnp41 mRNA nuclear export pathway","volume":"17","author":"PA Faria","year":"2005","journal-title":"Mol Cell"},{"issue":"5320","key":"pone.0312098.ref038","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1126\/science.276.5320.1845","article-title":"Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus","volume":"276","author":"LS Her","year":"1997","journal-title":"Science"},{"issue":"5559","key":"pone.0312098.ref039","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1126\/science.1067861","article-title":"Role of nucleoporin induction in releasing an mRNA nuclear export block","volume":"295","author":"J Enninga","year":"2002","journal-title":"Science"},{"issue":"7816","key":"pone.0312098.ref040","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"583","author":"DE Gordon","year":"2020","journal-title":"Nature"},{"issue":"2","key":"pone.0312098.ref041","doi-asserted-by":"crossref","first-page":"e00065","DOI":"10.1128\/mBio.00065-21","article-title":"SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98.","volume":"12","author":"A Addetia","year":"2021","journal-title":"mBio"},{"issue":"8","key":"pone.0312098.ref042","doi-asserted-by":"crossref","first-page":"e1010349","DOI":"10.1371\/journal.ppat.1010349","article-title":"SARS-CoV-2 ORF6 disrupts innate immune signalling by inhibiting cellular mRNA export.","volume":"18","author":"R Hall","year":"2022","journal-title":"PLoS Pathog."},{"key":"pone.0312098.ref043","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.bbrc.2020.11.115","article-title":"Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex","volume":"536","author":"K Kato","year":"2021","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0312098.ref044","doi-asserted-by":"crossref","first-page":"813248","DOI":"10.3389\/fmolb.2021.813248","article-title":"Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export.","volume":"8","author":"T Li","year":"2021","journal-title":"Front Mol Biosci."},{"issue":"1","key":"pone.0312098.ref045","doi-asserted-by":"crossref","first-page":"4782","DOI":"10.1038\/s41467-022-32489-5","article-title":"Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport.","volume":"13","author":"X Gao","year":"2022","journal-title":"Nat Commun."},{"issue":"5","key":"pone.0312098.ref046","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/emboj.2009.5","article-title":"Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA","volume":"28","author":"J Katahira","year":"2009","journal-title":"EMBO J"},{"issue":"5","key":"pone.0312098.ref047","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1083\/jcb.124.5.627","article-title":"Nuclear export of different classes of RNA is mediated by specific factors","volume":"124","author":"A Jarmolowski","year":"1994","journal-title":"J Cell Biol"},{"key":"pone.0312098.ref048","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/B978-0-12-417160-2.00018-7","article-title":"Analysis of RNA transport in Xenopus oocytes and mammalian cells","volume":"122","author":"I Taniguchi","year":"2014","journal-title":"Methods Cell 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A"},{"issue":"38","key":"pone.0312098.ref052","doi-asserted-by":"crossref","first-page":"8385","DOI":"10.1021\/acs.jpclett.3c01440","article-title":"Nanoscopic Elucidation of Spontaneous Self-Assembly of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Open Reading Frame 6 (ORF6) Protein.","volume":"14","author":"G Nishide","year":"2023","journal-title":"J Phys Chem Lett"},{"issue":"5","key":"pone.0312098.ref053","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.cell.2020.10.004","article-title":"SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses","volume":"183","author":"AK Banerjee","year":"2020","journal-title":"Cell"},{"issue":"7862","key":"pone.0312098.ref054","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/s41586-021-03610-3","article-title":"SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis","volume":"594","author":"Y 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