Abstract
Infection of hepatitis B virus (HBV) increase the incidence of chronic liver disease and hepatocellular carcinoma (HCC). The hepatitis B viral x (HBx) protein encoded by the HBV genome contributes to the pathogenesis of HCC and thus, negative regulation of HBx is beneficial for the alleviation of the disease pathogenesis. MARCH5 is a mitochondrial E3 ubiquitin ligase and here, we show that high MARCH5 expression levels are correlated with improved survival in HCC patients. MARCH5 interacts with HBx protein mainly accumulated in mitochondria and targets it for degradation. The N-terminal RING domain of MARCH5 was required for the interaction with HBx, and MARCH5H43W lacking E3 ligase activity failed to reduce HBx protein levels. High expression of HBx results in the formation of protein aggregates in semi-denaturing detergent agarose gels and MARCH5 mediates the elimination of protein aggregates through the proteasome pathway. HBx-induced ROS production, mitophagy, and cyclooxygenase-2 gene expression were suppressed in the presence of high MARCH5 expression. These results suggest MARCH5 as a target for alleviating HBV-mediated liver disease.
Highlights
The ubiquitin–proteasome pathway is an important system for the processing of abnormally folded or damaged proteins, and failure of protein quality control systems results in the accumulation of cytotoxic protein aggregates
MARCH5 expression is positively correlated with the survival rate of patients with liver tumors MARCH5 is a crucial regulator of mitochondrial dynamics and protein quality control[19]
The Cancer Genome Atlas (TCGA) data were used to analyze the role of MARCH5 expression in hepatocellular carcinoma (HCC) patient outcomes, which showed that MARCH5 mRNA expression was positively correlated with patient survival (Fig. 1c)
Summary
The ubiquitin–proteasome pathway is an important system for the processing of abnormally folded or damaged proteins, and failure of protein quality control systems results in the accumulation of cytotoxic protein aggregates. The inability of liver cells to eliminate protein aggregates plays a role in chronic liver diseases such as steatohepatitis and liver cancer[2]. Mallory–Denk bodies (MDBs) are hepatic inclusions containing keratin aggregates, and MDB formation is considered as a failure of protein quality control[3]. The HBV x protein (HBx) is a non-structural protein that plays an important role in hepatocytes, promoting the progression of liver disease in patients infected with HBV5. HBx exerts a potent transactivation effect, and acts on a wide range of viral and cellular regulatory DNA elements[6,7].
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