{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T14:35:15Z","timestamp":1788014115673,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010204","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the national natural science foundation of china","doi-asserted-by":"crossref","award":["81501755"],"award-info":[{"award-number":["81501755"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005063","name":"excellent young talents fund program of higher education institutions of anhui province","doi-asserted-by":"publisher","award":["2018-ZQN-58"],"award-info":[{"award-number":["2018-ZQN-58"]}],"id":[{"id":"10.13039\/501100005063","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the joint funds for the innovation of science and technology, fujian province","award":["2016Y9039"],"award-info":[{"award-number":["2016Y9039"]}]},{"DOI":"10.13039\/501100003392","name":"natural science foundation of fujian province","doi-asserted-by":"publisher","award":["2020J01603"],"award-info":[{"award-number":["2020J01603"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The hepatitis B virus (HBV) core protein (HBc) functions in multiple steps of the viral life cycle. Heteroaryldihydropyrimidine compounds (HAPs) such as Bay41-4109 are capsid protein allosteric modulators that accelerate HBc degradation and inhibit the virion secretion of HBV, specifically by misleading HBc assembly into aberrant non-capsid polymers. However, the subsequent cellular fates of these HAP-induced aberrant non-capsid polymers are not well understood. Here, we discovered that that the chaperone-binding E3 ubiquitin ligase protein STUB1 is required for the removal of Bay41-4109-induced aberrant non-capsid polymers from HepAD38 cells. Specifically, STUB1 recruits BAG3 to transport Bay41-4109-induced aberrant non-capsid polymers to the perinuclear region of cells, thereby initiating p62-mediated macroautophagy and lysosomal degradation. We also demonstrate that elevating the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of HBeAg and HBV virions in HepAD38 cells, in HBV-infected HepG2-NTCP cells, and in HBV transgenic mice. STUB1 overexpression also facilitates the inhibition of Bay41-4109 on the cccDNA formation in <jats:italic>de novo<\/jats:italic> infection of HBV. Understanding these molecular details paves the way for applying HAPs as a potentially curative regimen (or a component of a combination treatment) for eradicating HBV from hepatocytes of chronic infection patients.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010204","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T19:46:02Z","timestamp":1642189562000},"page":"e1010204","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy"],"prefix":"10.1371","volume":"18","author":[{"given":"Jiacheng","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia-Zhen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He-Chen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Yun","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"issue":"1","key":"ppat.1010204.ref001","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/17460441.2017.1255195","article-title":"The current status and future directions of hepatitis B antiviral drug discovery.","volume":"12","author":"L Tang","year":"2017","journal-title":"Expert opinion on drug discovery."},{"key":"ppat.1010204.ref002","doi-asserted-by":"crossref","first-page":"104917","DOI":"10.1016\/j.antiviral.2020.104917","article-title":"Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B","volume":"182","author":"U Viswanathan","year":"2020","journal-title":"Antiviral research"},{"issue":"20","key":"ppat.1010204.ref003","article-title":"Revisiting Hepatitis B Virus: Challenges of Curative Therapies","volume":"93","author":"J Hu","year":"2019","journal-title":"J Virol"},{"key":"ppat.1010204.ref004","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.antiviral.2015.06.020","article-title":"Core protein: A pleiotropic keystone in the HBV lifecycle","volume":"121","author":"A Zlotnick","year":"2015","journal-title":"Antiviral 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review of pharmacology and toxicology"},{"key":"ppat.1010204.ref036","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fnins.2017.00185","article-title":"Protein Quality Control by Molecular Chaperones in Neurodegeneration.","volume":"11","author":"A Ciechanover","year":"2017","journal-title":"Frontiers in neuroscience"},{"key":"ppat.1010204.ref037","first-page":"61","article-title":"Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus","author":"JM Berke","year":"2017","journal-title":"Antimicrobial agents and chemotherapy"},{"issue":"3","key":"ppat.1010204.ref038","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01695-20","article-title":"Characterization of Hepatitis B Precore\/Core-Related Antigens","volume":"95","author":"X Hong","year":"2021","journal-title":"J 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