{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:51:41Z","timestamp":1780491101735,"version":"3.54.1"},"reference-count":22,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation","award":["NRF-2018R1A5A1024340"],"award-info":[{"award-number":["NRF-2018R1A5A1024340"]}]},{"name":"National Research Foundation","award":["NRF-2022R1A2C3006522"],"award-info":[{"award-number":["NRF-2022R1A2C3006522"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Human coronaviruses (HCoVs) modify host proteins to evade the antiviral defense and sustain viral expansion. Here, we report tonicity-responsive enhancer (TonE) binding protein (TonEBP) as a cellular target of HCoVs. TonEBP was cleaved into N-terminal and C-terminal fragments (TonEBP NT and TonEBP CT, respectively) by NSP5 from all the HCoVs tested. This cleavage resulted in the loss of TonEBP\u2019s ability to stimulate the TonE-driven transcription. On the other hand, TonEBP NT promoted viral expansion in association with the suppression of IFN-\u03b2 expression. TonEBP NT competed away NF-\u03baB binding to the PRD II domain on the IFN-\u03b2 promoter. A TonEBP mutant resistant to the cleavage by NSP5 did not promote the viral expansion nor suppress the IFN-\u03b2 expression. These results demonstrate that HCoVs use a common strategy of targeting TonEBP to suppress the host immune defense.<\/jats:p>","DOI":"10.3390\/cells13191614","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T06:55:52Z","timestamp":1727333752000},"page":"1614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Gain-of-Function Cleavage of TonEBP by Coronavirus NSP5 to Suppress IFN-\u03b2 Expression"],"prefix":"10.3390","volume":"13","author":[{"given":"Hyun","family":"Park","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1182-5320","authenticated-orcid":false,"given":"Sang Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2611-6792","authenticated-orcid":false,"given":"Su Ji","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong Cheon","family":"Kweon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go Woon","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whi Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whaseon","family":"Lee-Kwon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5183-3665","authenticated-orcid":false,"given":"Chan Young","family":"Park","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3244-2025","authenticated-orcid":false,"given":"Hyug Moo","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12985-019-1182-0","article-title":"Coronavirus envelope protein: Current knowledge","volume":"16","author":"Schoeman","year":"2019","journal-title":"Virol. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2217\/fmb.10.166","article-title":"Human coronavirus NL63: A clinically important virus?","volume":"6","author":"Fielding","year":"2011","journal-title":"Future Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s41579-023-01003-z","article-title":"SARS-CoV-2 biology and host interactions","volume":"22","author":"Steiner","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pavan, M., and Moro, S. (2023). Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054401"},{"key":"ref_5","first-page":"162","article-title":"SARS-CoV-2 variant biology: Immune escape, transmission and fitness","volume":"21","author":"Carabelli","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","first-page":"178","article-title":"Innate immune evasion strategies of SARS-CoV-2","volume":"21","author":"Minkoff","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108628","DOI":"10.1016\/j.celrep.2020.108628","article-title":"MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells","volume":"34","author":"Yin","year":"2021","journal-title":"Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.immuni.2019.03.025","article-title":"Shared and Distinct Functions of Type I and Type III Interferons","volume":"50","author":"Lazear","year":"2019","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41590-019-0323-3","article-title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape","volume":"20","author":"Hubel","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, Y., Qin, C., Rao, Y., Ngo, C., Feng, J.J., Zhao, J., Zhang, S., Wang, T.Y., Carriere, J., and Savas, A.C. (2021). SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response. mBio, 12.","DOI":"10.1128\/mBio.02335-21"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41392-023-01418-3","article-title":"The main protease of SARS-CoV-2 downregulates innate immunity via a translational repression","volume":"8","author":"Liang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e0003722","DOI":"10.1128\/jvi.00037-22","article-title":"SARS-CoV-2 nsp5 Exhibits Stronger Catalytic Activity and Interferon Antagonism than Its SARS-CoV Ortholog","volume":"96","author":"Chen","year":"2022","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1016\/j.molcel.2022.04.033","article-title":"Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells","volume":"82","author":"Pinilla","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1080\/22221751.2020.1870414","article-title":"SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): Implications for disease presentation across species","volume":"10","author":"Moustaqil","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1073\/pnas.96.5.2538","article-title":"Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity","volume":"96","author":"Miyakawa","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Ye, X., Zhang, H.M., Hanson, P., Zhao, G., Tong, L., Xie, R., and Yang, D. (2017). Cleavage of osmosensitive transcriptional factor NFAT5 by Coxsackieviral protease 2A promotes viral replication. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006744"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"jem.20190449","DOI":"10.1084\/jem.20190449","article-title":"The transcription factor NFAT5 limits infection-induced type I interferon responses","volume":"217","author":"Traveset","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e28618","DOI":"10.1002\/jmv.28618","article-title":"Human coronavirus 3CL proteases cleave septins and disrupt Hedgehog signaling, causing ciliary dysfunction","volume":"95","author":"Lee","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"001558","DOI":"10.1099\/jgv.0.001558","article-title":"Targeting novel structural and functional features of coronavirus protease nsp5 (3CL(pro), M(pro)) in the age of COVID-19","volume":"102","author":"Roe","year":"2021","journal-title":"J. Gen. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47571","DOI":"10.1074\/jbc.M308795200","article-title":"Multiple domains of TonEBP cooperate to stimulate transcription in response to hypertonicity","volume":"278","author":"Lee","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S1074-7613(00)80003-5","article-title":"An antiviral mechanism of nitric oxide: Inhibition of a viral protease","volume":"10","author":"Saura","year":"1999","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1161\/01.CIR.0000136824.73458.20","article-title":"Protective role for interferon-beta in coxsackievirus B3 infection","volume":"110","author":"Deonarain","year":"2004","journal-title":"Circulation"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/19\/1614\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:03:50Z","timestamp":1760112230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/19\/1614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":22,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["cells13191614"],"URL":"https:\/\/doi.org\/10.3390\/cells13191614","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}