SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate

SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate Yan Gao, Lucas Lacerda Souza, Hong Soon Kang, Zehan Li, Juan Carlos Hernandez-Guerrero, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6073524/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract COVID-19 patients readily present with severe epithelial damage, such as tissue ulceration and erosion, along with disrupted tissue repair, in multiple organs. The mucous membranes of the lung alveoli 1,2 , gastrointestinal tract 3,4 , nasal 5 and oral cavity 6,7 are the primary targets of the SARS-CoV-2 virus. The infected epithelium triggers a dysregulated immune response that further damages tissues and organs 8-10 . Increasing evidence suggests that the SARS-CoV-2 virus can cause direct damage to epithelial cells and fibroblasts 11-13 . Here, we report that the mucosa epithelia of COVID-19 patients can undergo cellular dedifferentiation before any pathological features are observed. SARS-CoV-2 nonspikestructural proteins, particularly the Envelope protein, can rapidly induce epithelial cell dedifferentiation, micronuclei formation, cell cycle arrest at the G1 phase and apoptosis. The protein can also severely affect the progenitor cell stratification program. Mechanistically, we identified a unique molecule, calponin 2 (CNN2), as a downstream effector of nonspike structural proteins. Moreover, CNN2 levels were elevated in the epithelia of COVID-19 patients. Downregulating CNN2 could inhibit epithelial cell apoptosis and promote cell differentiation. CNN2 expression is negatively regulated by GLIS2, a transcription factor associated with the disruption of ciliary dynamics in epithelial cells. Therefore, we propose that SARS-CoV-2 damages mucosal epithelium integrity via a novel “double hijack” mechanism and suggest new therapeutic targets for COVID-19 treatment. COVID-19 SARS-CoV-2 Mucosa Epithelial Cells Cell Death Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6073524","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":418674420,"identity":"9b51eb70-6dd4-4e6d-9bc8-45e463a80e90","order_by":0,"name":"Yan Gao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Gao","suffix":""},{"id":418674421,"identity":"da7de316-1e8c-4a50-845d-21c22eb80113","order_by":1,"name":"Lucas Lacerda Souza","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lucas","middleName":"Lacerda","lastName":"Souza","suffix":""},{"id":418674422,"identity":"607576a7-4743-4412-aa67-1cf818fd3774","order_by":2,"name":"Hong Soon Kang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"Soon","lastName":"Kang","suffix":""},{"id":418674423,"identity":"08e5e261-3ff9-4a5c-90be-82248e608df0","order_by":3,"name":"Zehan Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Zehan","middleName":"","lastName":"Li","suffix":""},{"id":418674424,"identity":"0e5ece1d-1f96-4d1b-9a87-b12c394c1b3d","order_by":4,"name":"Juan Carlos Hernandez-Guerrero","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"Carlos","lastName":"Hernandez-Guerrero","suffix":""},{"id":418674425,"identity":"542c4cdd-5f5a-45a5-9524-38ab918f614a","order_by":5,"name":"Fábio Abreu Alves","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Fábio","middleName":"Abreu","lastName":"Alves","suffix":""},{"id":418674426,"identity":"b5ff237d-faed-43f4-a335-86f275c60856","order_by":6,"name":"Wei Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhang","suffix":""},{"id":418674427,"identity":"95d2bb69-b5d7-4a71-bc28-f237df55d2c4","order_by":7,"name":"Vikram Sharma","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vikram","middleName":"","lastName":"Sharma","suffix":""},{"id":418674428,"identity":"e77e68f4-0e6d-4831-878d-87242c584dab","order_by":8,"name":"Sally Hanks","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sally","middleName":"","lastName":"Hanks","suffix":""},{"id":418674429,"identity":"cf285ff0-d311-4e5a-9686-1ec558c4e939","order_by":9,"name":"Jinhua Yu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jinhua","middleName":"","lastName":"Yu","suffix":""},{"id":418674430,"identity":"a896c734-2aee-48ce-9437-345f769b2cb8","order_by":10,"name":"Christopher Tredwin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Tredwin","suffix":""},{"id":418674431,"identity":"945fcf13-785a-4233-82ba-fdece598773d","order_by":11,"name":"Anton M. 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The mucous membranes of the lung alveoli\u0026nbsp;\u003csup\u003e1,2\u003c/sup\u003e, gastrointestinal tract\u0026nbsp;\u003csup\u003e3,4\u003c/sup\u003e, nasal\u0026nbsp;\u003csup\u003e5\u003c/sup\u003eand\u0026nbsp;oral cavity\u0026nbsp;\u003csup\u003e6,7\u003c/sup\u003e\u0026nbsp;are\u0026nbsp;the\u0026nbsp;primary\u0026nbsp;targets\u0026nbsp;of the SARS-CoV-2 virus. The infected epithelium triggers\u0026nbsp;a\u0026nbsp;dysregulated immune response that further\u0026nbsp;damages\u0026nbsp;tissues and organs\u0026nbsp;\u003csup\u003e8-10\u003c/sup\u003e. Increasing evidence\u0026nbsp;suggests\u0026nbsp;that the SARS-CoV-2 virus can cause direct\u0026nbsp;damage to\u0026nbsp;epithelial cells and fibroblasts\u0026nbsp;\u003csup\u003e11-13\u003c/sup\u003e. Here,\u0026nbsp;we report that the\u0026nbsp;mucosa epithelia of\u0026nbsp;COVID-19\u0026nbsp;patients\u0026nbsp;can undergo cellular dedifferentiation before any pathological features\u0026nbsp;are\u0026nbsp;observed. SARS-CoV-2\u0026nbsp;nonspikestructural proteins, particularly the\u0026nbsp;Envelope\u0026nbsp;protein,\u0026nbsp;can rapidly induce epithelial cell dedifferentiation, micronuclei formation, cell cycle arrest at\u0026nbsp;the\u0026nbsp;G1 phase and apoptosis. The protein can also severely affect\u0026nbsp;the\u0026nbsp;progenitor cell stratification program. Mechanistically, we identified a unique\u0026nbsp;molecule, calponin\u0026nbsp;2 (CNN2),\u0026nbsp;as a downstream effector of\u0026nbsp;nonspike\u0026nbsp;structural proteins. Moreover, CNN2 levels were elevated in the\u0026nbsp;epithelia of\u0026nbsp;COVID-19\u0026nbsp;patients. Downregulating\u0026nbsp;CNN2 could inhibit epithelial cell apoptosis and promote cell differentiation. CNN2 expression is negatively regulated by GLIS2, a\u0026nbsp;transcription\u0026nbsp;factor associated with the disruption of ciliary dynamics in epithelial cells. Therefore, we propose that SARS-CoV-2 damages\u0026nbsp;mucosal\u0026nbsp;epithelium integrity via a novel “double hijack” mechanism and suggest new therapeutic targets\u0026nbsp;for\u0026nbsp;COVID-19 treatment.\u003c/p\u003e","manuscriptTitle":"SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-26 04:01:07","doi":"10.21203/rs.3.rs-6073524/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bb2f55d8-7c40-429a-8fcc-a69fc0f41add","owner":[],"postedDate":"February 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-25T22:10:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-26 04:01:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6073524","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6073524","identity":"rs-6073524","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}