{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:03:34Z","timestamp":1787022214551,"version":"build-2736575974"},"reference-count":106,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI110762"],"award-info":[{"award-number":["R01AI110762"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI134818"],"award-info":[{"award-number":["R01AI134818"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA047904"],"award-info":[{"award-number":["P30CA047904"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100030715","name":"Hillman Cancer Center, Medical Center, University of Pittsburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100030715","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pitt-Tsinghua Biomedical Scholars Program"},{"name":"Intramural Research Program of the National Institutes of Health","award":["None"],"award-info":[{"award-number":["None"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The circulating hepatitis B virus (HBV) e antigen (HBeAg) is known to subvert the host immune system to benefit chronic HBV infection. However, the biological function of a major intracellular form of HBeAg, specifically the precore protein intermediate of 22\u2009kDa (p22) lacking the N-terminal signal peptide, remains largely unclear. Through pull-down and mass spectrometry analysis, we re-identified the complement C1q binding protein (C1QBP) as a p22-binding protein. Immunofluorescence results demonstrated that C1QBP was predominantly localized in the mitochondrial matrix and the leaked C1QBP interacted with p22 in the cytosol. Using co-immunoprecipitation assay, we mapped the arginine-rich, highly positively charged C-terminal domain (CTD) of p22 and the internal domain aa 74\u2013160 of C1QBP as binding domains for p22-C1QBP interaction. By studying the impact of C1QBP on HBV replication, we found that C1QBP overexpression led to the autolysosomal degradation of HBV core protein (HBc) and significantly reduced viral nucleocapsid formation in a p22-dependent manner. Additionally, a C1QBP mutant without the mitochondrial targeting signal (MTS) exhibited a greater inhibitory effect on HBV replication compared to the wild type (wt). Although HBc and p22 share the same CTD sequence, C1QBP does not bind to wt HBV capsid. However, disrupting capsid assembly by HBc-Y132A mutant or CAM-A (class A capsid assembly modulator) treatment enables HBc-C1QBP interaction. Moreover, C1QBP binds to the CTD of HBc on the cytoplasmic deproteinated relaxed circular DNA (DP-rcDNA)-containing capsid that is partially disassembled, hindering DP-rcDNA nuclear import and subsequent covalently closed circular DNA (cccDNA) formation. Collectively, our study suggests that C1QBP inhibits HBV replication through dual mechanisms, proposing a novel therapeutic approach for managing chronic HBV infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013581","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:40:41Z","timestamp":1760722841000},"page":"e1013581","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["HBV p22-interacting protein C1QBP inhibits viral replication through impeding nucleocapsid formation and nuclear import"],"prefix":"10.1371","volume":"21","author":[{"given":"Xiao","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Der","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bidisha","family":"Mitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena S.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Jurado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shitao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongqing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7146-916X","authenticated-orcid":true,"given":"Haitao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"issue":"4","key":"ppat.1013581.ref001","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.cld.2007.08.002","article-title":"Molecular 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