{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:31:18Z","timestamp":1772253078101,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008386","name":"Marmara University Research Fund","doi-asserted-by":"publisher","award":["SAG-B-130319-0089"],"award-info":[{"award-number":["SAG-B-130319-0089"]}],"id":[{"id":"10.13039\/501100008386","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SLO"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC), the most common primary liver malignancy worldwide, is strongly associated with chronic Hepatitis B Virus (HBV) infection, a significant risk factor. The ubiquitin\u2013proteasome system, central to protein degradation, cellular homeostasis, and cell cycle regulation, has been implicated in the pathogenesis of several cancers, including HCC. Despite this, the specific expression patterns of proteasomal subunits during HBV infection and HBV-induced HCC, as well as the association between mRNA expression of proteasomal subunits and proteasomal activity, remain poorly defined. To address this critical knowledge gap, we analyzed mRNA expression profiles of proteasomal subunits in HBV-infected humanized mouse models to uncover HBV-specific molecular alterations. Our findings revealed that the chymotrypsin-like activity (\u03b25) subunit of the proteasome (PSMB5) is consistently overexpressed following HBV infection. Functional studies demonstrated that \u03b25 deficiency decreases MHC I levels on the cell surface and leads to the accumulation of ubiquitinated proteins, establishing a direct link between \u03b25 overexpression and increased proteasomal activity. Concordantly, HBV-infected patient livers\u2014regardless of HCC status\u2014displayed elevated \u03b25 mRNA\/protein levels and enhanced chymotrypsin-like activity. Additionally, analysis of Protein Atlas data revealed that elevated \u03b25 mRNA expression correlates with poor clinical prognosis in HCC patients. In summary, this study highlights how HBV infection induces significant alterations in proteasome function by elevating \u03b25 expression and activity in human and mouse livers. These findings underscore the critical role of proteasomal dysregulation in HBV-associated liver pathology and provide new insights into its involvement in HCC development. Understanding the interplay between HBV infection and proteasome dynamics offers a valuable avenue for the identification of novel therapeutic targets and biomarkers in HCC.<\/jats:p>","DOI":"10.3390\/v17111454","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:47:58Z","timestamp":1762177678000},"page":"1454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HBV Infection Drives PSMB5-Dependent Proteasomal Activation in Humanized Mice and HBV-Associated HCC"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-6893","authenticated-orcid":false,"given":"Ayse Tarbin","family":"Jannuzzi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, Istanbul University, Istanbul 34116, Turkey"},{"name":"Department of Biochemistry, School of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul 34854, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-5889","authenticated-orcid":false,"given":"Gulce","family":"Sari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul 34854, Turkey"},{"name":"Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sema","family":"Arslan-Eseryel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul 34854, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mujdat","family":"Zeybel","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, School of Medicine, Koc University, Istanbul 34450, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4518-5283","authenticated-orcid":false,"given":"Yusuf","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, School of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53200, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-7233","authenticated-orcid":false,"given":"Murat","family":"Dayangac","sequence":"additional","affiliation":[{"name":"Department of General Surgery, International School of Medicine, Istanbul Medipol University, Istanbul 34810, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Buket","family":"Yigit","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, School of Medicine, Koc University, Istanbul 34450, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-1348","authenticated-orcid":false,"given":"Kazim Yalcin","family":"Arga","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Marmara University, Istanbul 34854, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8607-1616","authenticated-orcid":false,"given":"Andre","family":"Boonstra","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8126-2413","authenticated-orcid":false,"given":"Fatih","family":"Eren","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, School of Medicine, Marmara University, Istanbul 34854, Turkey"},{"name":"Department of Medical Biology, School of Medicine, Recep Tayyip Erdogan University, Rize 53200, Turkey"},{"name":"Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul 34854, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-0284","authenticated-orcid":false,"given":"Betul","family":"Karademir-Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul 34854, Turkey"},{"name":"Department of Biochemistry, School of Medicine, Recep Tayyip Erdogan University, Rize 53200, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.mam.2009.04.001","article-title":"The proteasomal system","volume":"30","author":"Jung","year":"2009","journal-title":"Mol. 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