Investigating the Expression and the Activity Patterns of Proteasomal Subunits in Livers with HBV infection and HBV-Derived HCC

Author:

Januzzi Ayse Tarbin1,Sari Gulce2ORCID,Arslan-Eseryel Sema3,Zeybel Mujdat4,Yilmaz Yusuf5,Dayangac Murat6,Yigit Buket4,Arga Kazim Yalcin7,Boonstra Andre8,Eren Fatih9,Karademir-Yilmaz Betul3

Affiliation:

1. 1 Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Türkiye 2 Department of Biochemistry, Faculty of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul, Türkiye #shared first author

2. 2 Department of Biochemistry, Faculty of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul, Türkiye 3 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands, #shared first author

3. 2 Department of Biochemistry, Faculty of Medicine & Genetic and Metabolic Disease Research and Investigation Center, Marmara University, Istanbul, Türkiye

4. 4 Department of Gastroenterology and Hepatology, School of Medicine, Koc University, Istanbul, Türkiye

5. 5 Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye

6. 6 Department of General Surgery, International School of Medicine, Istanbul Medipol University, Istanbul, Türkiye

7. 7 Department of Bioengineering, Marmara University, Istanbul, Turkey

8. 3 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands

9. 8 Department of Medical Biology, Faculty of Medicine, Marmara University, Istanbul, Türkiye 9 Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Türkiye 10 Institute of Gastroenterology, Liver Research Unit, Marmara University, Istanbul, Türkiye

Abstract

Abstract

Background & Aims: Hepatocellular Carcinoma (HCC) is the most prevalent types of liver cancer worldwide, with chronic infection of Hepatitis B Virus (HBV) being a major risk factor. The ubiquitin-proteasome system plays a critical role in protein degradation, cellular homeostasis, and cell cycle regulation. Dysregulation of proteasomal activity has been implicated in various cancers, including HCC. However, the specific expression patterns of proteasomal subunits in HBV infection and HBV-induced HCC remain poorly understood. Additionally, it is not known whether the mRNA expression of proteasome subunits correlates with the activity. Methods & Results: To fill this knowledge gap, we analyzed the proteasomal subunit mRNA expression levels in a liver-humanized mouse model after HBV infection. We found that the chymotrypsin-like activity (β5) subunit of the proteasome (PSMB5) was overexpressed after HBV infection. β5-deficient cells showed lower cell surface MHC I levels and increased accumulation of ubiquitinated proteins indicating an expression-function correlation. Similar to the mRNA expression data, protein levels of β5 subunit was higher in HBV-infected patient livers, and the infected liver tissue showed higher chymotrypsin-like proteolytic activity. The Protein Atlas data analysis also indicated that higher mRNA expression of β5 is associated with poor prognosis in HCC. Conclusions In summary, HBV infection increases both protein levels and the proteolytic activity of proteasomes in infected livers. The dynamics of protein degradation by proteasomes in HBV infected livers with HCC is of great importance to be able to develop better treatment strategies.

Publisher

Springer Science and Business Media LLC

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