{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:21:22Z","timestamp":1788430882490,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background and objective<\/jats:title>\n                    <jats:p>Type I interferon (IFN-I) signaling is crucial for antiviral innate immunity. F-box protein-mediated ubiquitination regulates this pathway. FBXO11 positively regulates IFN-I signaling via TRAF3 K63-linked ubiquitination, but whether other F-box proteins act synergistically during HBV infection remains unknown. This study investigates FBXO32 expression and function in HBV infection, and whether FBXO11 and FBXO32 synergistically activate innate immunity through a NEDD8-dependent mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Immunofluorescence (IF) staining for HBcAg and HBsAg confirmed successful HBV infection. qRT-PCR screening of 14 FBXO family members in HBV-infected HepG2-NTCP cells identified FBXO11 and FBXO32 as the most markedly upregulated. Cellular loss- and gain-of-function studies (single or double knockout and overexpression) were performed, followed by qRT\u2212PCR and western blot analysis of antiviral genes. Mechanistically, co-immunoprecipitation was used to assess FBXO11\/FBXO32 interactions with TRAF3, TBK1, and IRF3, and the NEDD8 inhibitor MLN4924 was applied to confirm NEDD8 dependence.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , to distinguish progeny viral DNA from the injected plasmid, a control experiment was performed in which the vector backbone sequence of the pAAV\/HBV1.2 plasmid was detected alongside the HBV gene. Subsequently, hydrodynamic tail-vein injection of the pAAV\/HBV1.2 plasmid was performed in C57BL\/6 mice with single or double knockout or overexpression of FBXO11 and FBXO32.Serum and liver samples were collected at 0, 6, 12, 24, and 48 hours post-infection to quantify HBV DNA (qPCR), HBsAg, HBeAg and HBcAg (ELISA). Liver pathology was evaluated by H&amp;amp;E staining, and immunohistochemistry (IHC) for HBcAg, ISG56 and CXCL10 was performed on liver tissue sections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HBV infection markedly upregulated FBXO11 and FBXO32. Double knockout suppressed antiviral genes more strongly than single knockout. Mechanistically, FBXO11 and FBXO32 cooperatively enhanced NEDD8-dependent K63-linked ubiquitination of TRAF3, promoting TRAF3-TBK1-IRF3 complex assembly. Control experiments confirmed that the detected HBV DNA predominantly represented progeny virus rather than input plasmid. Based on this validated system, double knockout of FBXO11 and FBXO32 exacerbated liver pathology and elevated viral antigens, whereas double overexpression alleviated pathology and reduced antigens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>FBXO11 and FBXO32 synergistically enhance antiviral innate immunity by promoting NEDD8-dependent K63-linked TRAF3 ubiquitination, suppressing HBV replication and alleviating immunopathology. These findings reveal a synergistic anti-HBV axis and provide a potential therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1833429","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:07:00Z","timestamp":1788430020000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FBXO11 and FBXO32 synergistically activate innate immunity against hepatitis B virus in a NEDD8-dependent manner"],"prefix":"10.3389","volume":"17","author":[{"given":"Liqiang","family":"Li","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]},{"name":"Department of General Surgery, Hefei Second People\u2019s Hospital Affiliated to Bengbu Medical University","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00760-9","article-title":"Global burden of hepatitis B virus: current status, missed opportunities and a call for action","volume":"20","author":"Hsu","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2023.05.003","article-title":"Overview of new targets for hepatitis B virus: 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