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Review
. 2017 Apr 3;9(4):69.
doi: 10.3390/v9040069.

Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6

Christine M Livingston  1 , Dhivya Ramakrishnan  2 , Michel Strubin  3 , Simon P Fletcher  4 , Rudolf K Beran  5
Affiliations
Review

Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6

Christine M Livingston et al. Viruses. .

Abstract

Hepatitis B X protein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function of HBx has been elusive until recently. It was recently shown that transcription from the HBV genome (covalently-closed circular DNA, cccDNA) is inhibited by the structural maintenance of chromosome 5/6 complex (Smc5/6), and that a key function of HBx is to redirect the DNA-damage binding protein 1 (DDB1) E3 ubiquitin ligase to target this complex for degradation. By doing so, HBx alleviates transcriptional repression by Smc5/6 and stimulates HBV gene expression. In this review, we discuss in detail how the interplay between HBx and Smc5/6 was identified and characterized. We also discuss what is known regarding the repression of cccDNA transcription by Smc5/6, the timing of HBx expression, and the potential role of HBx in promoting hepatocellular carcinoma (HCC).

Keywords: DDB1; HBV; HBx; Smc5/6; cccDNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A cartoon representation of structural maintenance of chromosome 5/6 complex (Smc5/6). Smc5/6 is composed of Smc5, Smc6, Nse1, Nse2, Nse3, and Nse4.
Figure 2
Figure 2
A model depicting the role of hepatitis B X protein (HBx) in hepatitis B virus (HBV) infection of a human hepatocyte. Relaxed-circular DNA (rcDNA) and possibly HBx RNA are deposited within the cell, and HBx protein may be translated from the HBx RNA. rcDNA is converted to covalently-closed circular DNA (cccDNA) and HBx binds Cullin4–DNA-damage binding protein1 (Cul4–DDB1). Structural maintenance of chromosomes 5/6 (Smc5/6) co-localizes with nuclear domain 10 (ND10) bodies. Cul4–DDB1–HBx targets Smc5/6 for ubiquitination. Smc5/6 is subsequently degraded by the proteasome, and cccDNA can now be transcribed.
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