{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T09:51:09Z","timestamp":1768989069732,"version":"3.49.0"},"reference-count":67,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82372249"],"award-info":[{"award-number":["82372249"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Natural Science Fund for Excellent Young Scientists Fund Program"},{"name":"The Start-up funding from Life Sciences Institute, Zhejiang University"},{"DOI":"10.13039\/100022955","name":"Fundamental Research Funds for the Provincial Universities of Zhejiang","doi-asserted-by":"crossref","award":["K20240145"],"award-info":[{"award-number":["K20240145"]}],"id":[{"id":"10.13039\/100022955","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100022955","name":"Fundamental Research Funds for the Provincial Universities of Zhejiang","doi-asserted-by":"crossref","award":["20230QZJH60"],"award-info":[{"award-number":["20230QZJH60"]}],"id":[{"id":"10.13039\/100022955","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,1,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Enteroviral 3C protease (3Cpro) is an essential enzyme for viral replication and is responsible for combating the host anti-viral immune response by targeting cellular proteins for cleavage. The identification and characterization of 3Cpro substrates will contribute to our understanding of viral pathogenesis. In this study, we performed a motif search for 3Cpro substrates in the human protein database using FIMO, which refers to a common cleavage sequence of 3Cpro. We identified and characterized NEDD4-binding protein 1 (N4BP1), a key negative regulator of the NF-\u03baB pathway, as a novel 3Cpro substrate. N4BP1 is cleaved at residue Q816 by 3Cpro from several human enteroviruses, resulting in the loss of its ability to regulate tumor necrosis factor alpha-activated NF-\u03baB signaling. In addition, we found that mouse N4BP1, which has a threonine at the P1\u2032 site, is resistant to human enteroviral 3Cpro cleavage. However, rodent enteroviral 3Cpro derived from encephalomyocarditis virus (EMCV) can cleave both human and mouse N4BP1 at a species-specific site. By combining bioinformatic, biochemical, and cell biological approaches, we identified and characterized N4BP1 as a novel substrate of enteroviral 3Cpro. These findings provide valuable insights into the interplay between 3Cpro, its substrates, and viral pathogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Targeting cellular proteins for cleavage by enteroviral 3Cpro is a conserved strategy used by enteroviruses to promote viral replication. While the cleavage of certain host proteins by 3Cpro may not affect viral replication, it is strongly associated with the pathogenesis of viral infection. In this study, we identified and characterized N4BP1, which plays such a role, using a combination of bioinformatic, biochemical, and cell biological approaches. Our data show that multiple 3Cpros cleave N4BP1 at residue Q816 and that cleavage of endogenous N4BP1 can occur during viral infection. N4BP1 has no effect on coxsackievirus B3 replication, but 3Cpro-induced N4BP1 cleavage abolishes its regulatory function in NF-\u03baB signaling. We also show that mouse N4bp1 resists human enteroviral 3Cpro cleavage. In contrast, rodent enteroviral EMCV 3Cpro can target human and mouse N4BP1 for cleavage at different residues, which indicates that future investigations are needed to elucidate the potential mechanisms involved.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01758-24","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T14:02:18Z","timestamp":1733839338000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Enteroviral 3C protease cleaves N4BP1 to impair the host inflammatory response"],"prefix":"10.1128","volume":"99","author":[{"given":"Dongjie","family":"Zhang","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University","place":["Hangzhou, 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