Abstract
Hepatitis B virus (HBV) is a widespread human pathogen that often causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The detailed mechanisms underlying HBV pathogenesis remain poorly understood. The HBV X protein (HBx) is a multifunctional regulator that modulates viral replication and host cell functions, such as cell cycle progression, apoptosis and protein degradation through interaction with a variety of host factors. Recently, the nonstructural protein 5A (NS5A) of hepatitis C virus has been reported to interact with methyltransferase SET and MYND domain-containing 3 (SMYD3), which is implicated in chromatin modification and development of cancer. Because HBx shares fundamental regulatory functions concerning viral replication and pathogenesis with NS5A, it was decided to examine whether HBx interacts with SMYD3. In the present study, it was demonstrated by co-immunoprecipitation analysis that HBx interacts with both ectopically and endogenously expressed SMYD3 in Huh-7.5 cells. Deletion mutation analysis revealed that the C-terminal region of HBx (amino acids [aa] 131-154) and an internal region of SMYD3 (aa 269-288) are responsible for their interaction. Immunofluorescence and proximity ligation assays showed that HBx and SMYD3 co-localize predominantly in the cytoplasm. Luciferase reporter assay demonstrated that the interaction between HBx and SMYD3 activates activator protein 1 (AP-1) signaling, but not that of nuclear factor-kappa B (NF-κB). On the other hand, neither overexpression nor knockdown of SMYD3 altered production of HBV transcripts and HBV surface antigen (HBsAg). In conclusion, a novel HBx-interacting protein, SMYD3, was identified, leading to proposal of a novel mechanism of AP-1 activation in HBV-infected cells.
Highlights
Hepatitis B virus (HBV) infection is a global public health problem, with more than 350 million people being chronically infected and at risk for developing serious liver disease, including chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]
We confirmed that HBV X protein (HBx) expressed in the context of HBV replication interacted with Flag-tagged SET and MYND domain-containing th 3 (SMYD3) using anti-Flag (Fig. 1c) and anti-HBx antibodies (Fig. 1d)
We found that a C-terminal region of HBx and an internal region of SMYD3 were involved in the r interaction (Fig. 2)
Summary
Hepatitis B virus (HBV) infection is a global public health problem, with more than 350 million people being chronically infected and at risk for developing serious liver disease, including chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]. HBx, a small protein of 17 kDa, is a t multifunctional regulator that modulates viral replication and host cell functions, such rip as cell cycle progression, apoptosis and protein degradation [7, 8]. HBx interacts with a sc variety of cellular proteins and plays important roles in both virus replication and u pathogenesis. M Recently, it was reported that the methyltransferase SET and MYND domain-containing th 3 (SMYD3) is a binding partner of the nonstructural protein 5A (NS5A) of hepatitis C Au virus (HCV), which is a multifunctional protein interacting with various host factors, and plays pivotal roles in viral replication and assembly [11]. SMYD3 was recently shown to methylate non-histone proteins, such as mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to promote the development of Ras-driven cancer [14]. We report here that HBx interacts with SMYD3 and facilitates SMYD3-mediated activator protein 1 (AP-1) activation
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