{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:41:31Z","timestamp":1792503691229,"version":"4.5.0"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372231"],"award-info":[{"award-number":["82372231"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302503"],"award-info":[{"award-number":["82302503"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFC2311000"],"award-info":[{"award-number":["2024YFC2311000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Joint Funds For the Innovation of Science and Technology in Fujian Province","award":["2023Y9002"],"award-info":[{"award-number":["2023Y9002"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Post-translational modifications orchestrate virus\u2013host interactions, yet their roles in the hepatitis B virus (HBV) life cycle remain incompletely defined. The small hepatitis B surface antigen (SHBs)\u2014the most abundant HBV protein\u2014drives immune evasion, pathogenesis, and virion\/subviral particle (SVP) production. Here, we identify UFL1, the E3 ligase of UFMylation, as a host factor that modifies and stabilizes SHBs by antagonizing its ubiquitination to potentiate HBV output and SHBs-driven pro-oncogenic activities. Using affinity purification-mass spectrometry, we discovered UFL1 as a SHBs interactor and validated the interaction by co-immunoprecipitation, confocal co-localization, and GST pull-down assays.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      UFMylation assays demonstrated that UFL1 catalyzes SHBs\u2019 UFMylation. Site-directed mutagenesis mapped the modification to K122; the K122R mutant failed to undergo UFMylation. Cycloheximide chase and ubiquitination assays showed that UFMylation at K122 stabilizes SHBs by antagonizing TRIM21-mediated K48-linked polyubiquitination and proteasomal degradation. Functionally, UFL1 enhanced SHBs-driven hepatocellular carcinoma cell migration and endothelial tube formation, whereas UFL1 knockdown produced opposite effects. In HBV-producing cells, UFL1 increased intracellular and extracellular HBsAg and HBV virions, with no effects on HBV RNA, indicating post-translational control of HBsAg and virion\/SVP production. These findings establish SHBs as, to our knowledge, the first HBV protein substrate of UFMylation and reveal a UFL1-SHBs axis that promotes SHBs stability, pathogenic functions, and HBV particle output. Targeting UFMylation or the UFL1-SHBs interface offers a host-directed strategy to reduce HBsAg and virion production and may inform therapeutic approaches for HBV infection and HBV-related liver disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Chronic infection with hepatitis B virus (HBV) remains a major global health problem, in part because current treatments rarely reduce the viral surface protein that floods the blood and helps the virus persist. In this study, we asked how the most abundant viral surface protein\u2014SHBs\u2014is controlled inside cells. We discovered that UFL1 attaches a small \u201cmolecular tag\u201d as UFM1 to this viral protein, and this tag protects the SHBs from the cell\u2019s disposal system. As a result, the increased SHBs promotes behaviors linked to liver disease progression, and cells release more virion\/SVPs. When we prevented this tagging event or changed a single amino acid on the SHBs so it could not be tagged, the protein became unstable and was degraded, and virus output dropped. Thus, to our knowledge, SHBs is the first identified HBV protein substrate of UFMylation, suggesting targeting the UFL1-SHBs interface may reduce HBsAg and virion production and inform HBV therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01034-26","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:01:22Z","timestamp":1790082082000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["UFMylation of SHBs increases protein stability by antagonizing ubiquitination and promotes virion production"],"prefix":"10.1128","volume":"100","author":[{"given":"Shuxiang","family":"Wu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohuang","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjian","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5346-4605","authenticated-orcid":true,"given":"Xu","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education","place":["Fuzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/050s6ns64","id-type":"ROR","asserted-by":"publisher"}],"name":"Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"World Health Organization. 2021. 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