{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T03:26:05Z","timestamp":1792985165008,"version":"4.5.0"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"\u798f\u5efa\u7701\u79d1\u6280\u5385 | Natural Science Foundation of Fujian Province","award":["2023J02015"],"award-info":[{"award-number":["2023J02015"]}]},{"name":"Joint Funds for the Innovation of Science and Techonology, Fujian Province","award":["2020Y9004"],"award-info":[{"award-number":["2020Y9004"]}]},{"name":"Foundation of Fujian Provincial Finance Department","award":["22SCZZX016"],"award-info":[{"award-number":["22SCZZX016"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2023,11,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Chronic hepatitis B virus (HBV) infection represents an important global public health concern. The spliced variants generated by RNA splicing from 3.5-kb HBV pre-genomic RNA are involved in chronic hepatitis B pathogenicity and associated with hepatocellular carcinoma development. Although the HBV spliced variants with a length of 2.2 kb have been widely detected, their roles in the development of HBV-associated liver diseases remain unknown. In the present study, the pro-apoptotic effects of hepatitis B doubly spliced protein (HBDSP) encoded by 2.2-kb doubly spliced variants of HBV in wild-type\n            <jats:italic>p53<\/jats:italic>\n            (wt\n            <jats:italic>-p53<\/jats:italic>\n            ) hepatocytes were determined. We primarily found that HBDSP promoted the apoptosis of HepG2 and SMMC-7721 cells with wt\n            <jats:italic>-p53<\/jats:italic>\n            . The role of wt-\n            <jats:italic>p53<\/jats:italic>\n            in HBDSP-induced apoptosis was further investigated. It was demonstrated that HBDSP upregulated p53 and phospho-p53 (Ser15) expression and herein stimulated the\n            <jats:italic>p53<\/jats:italic>\n            -dependent apoptotic signaling pathway. Mechanistically, HBDSP indirectly transactivated the\n            <jats:italic>p53<\/jats:italic>\n            promoter in an ETS1-, GATA2-, and YY1-dependent manner, in which HBDSP increased the nuclear translocation of ETS1, GATA2, and YY1. Besides, it was demonstrated that HBDSP could promote cellular apoptosis and activate\n            <jats:italic>p53<\/jats:italic>\n            -dependent apoptotic signaling pathway, resulting in increased secretion of HBV DNA, HBsAg, and HBeAg in HepG2.2.15 cells and HBV-infected HepG2-NTCP cells. Taken together, our results reveal a novel mechanism by which HBDSP promotes ETS1\/GATA2\/YY1-dependent\n            <jats:italic>p53<\/jats:italic>\n            gene transcription and induces apoptosis in wt-\n            <jats:italic>p53<\/jats:italic>\n            cells, and increases the production of HBV progeny and viral antigens. These findings may provide novel insight into the pathogenesis of HBDSP involved in HBV-associated liver diseases.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Hepatitis B virus (HBV) spliced variants are associated with viral persistence or pathogenicity. Hepatitis B doubly spliced protein (HBDSP), which has been previously reported as a pleiotropic transactivator protein, can potentially serve as an HBV virulence factor. However, the underlying mechanisms of HBDSP in HBV-associated liver diseases remain to be elucidated. In this study, we revealed that HBDSP promotes cellular apoptosis and induces wt-\n              <jats:italic>p53<\/jats:italic>\n              -dependent apoptotic signaling pathway in wt-\n              <jats:italic>p53<\/jats:italic>\n              hepatocellular cells by transactivating p53 transcription, and increases the release of HBV progeny. Therefore, HBDSP may promote the HBV particles release through wt-\n              <jats:italic>p53<\/jats:italic>\n              -dependent hepatocellular apoptosis. Our findings suggest that blocking HBDSP-induced wt-\n              <jats:italic>p53<\/jats:italic>\n              -dependent apoptosis might have therapeutic values for chronic hepatitis B.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01087-23","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T13:01:23Z","timestamp":1699275683000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Hepatitis B doubly spliced protein (HBDSP) promotes hepatocellular carcinoma cell apoptosis via ETS1\/GATA2\/YY1-mediated p53 transcription"],"prefix":"10.1128","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-4624","authenticated-orcid":false,"given":"Xiazhen","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian 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