Hepatitis B Virus X Protein Promotes Degradation of SMC5/6 to Enhance HBV Replication

Murphy, Christopher M.; Xu, Yanping; Li, Feng; Nio, Kouki; Reszka-Blanco, Natalia; Li, Xiaodong; Wu, Yaxu; Yu, Yonghao; Xiong, Yue; Su, Lishan

doi:10.1016/j.celrep.2016.08.026

Cited by 257 publications

(288 citation statements)

References 38 publications

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“…While the hepatocyte innate immune response to HBV is poorly understood [34], it was recently demonstrated that HBV cccDNA is transcriptionally silenced by the Smc5/6 complex when HBx is not present [13,35]. However, it is not known how Smc5/6 suppresses viral gene expression or whether depletion of this complex plays a role in evasion of innate immunity or HBV pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

et al. 2017

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The structural maintenance of chromosome 5/6 complex (Smc5/6) is a restriction factor that represses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing HBV X protein (HBx), which targets Smc5/6 for degradation. However, the mechanism by which Smc5/6 suppresses HBV transcription and how HBx is initially expressed is not known. In this study we characterized viral kinetics and the host response during HBV infection of primary human hepatocytes (PHH) to address these unresolved questions. We determined that Smc5/6 localizes with Nuclear Domain 10 (ND10) in PHH. Co-localization has functional implications since depletion of ND10 structural components alters the nuclear distribution of Smc6 and induces HBV gene expression in the absence of HBx. We also found that HBV infection and replication does not induce a prominent global host transcriptional response in PHH, either shortly after infection when Smc5/6 is present, or at later times post-infection when Smc5/6 has been degraded. Notably, HBV and an HBx-negative virus establish high level infection in PHH without inducing expression of interferon-stimulated genes or production of interferons or other cytokines. Our study also revealed that Smc5/6 is degraded in the majority of infected PHH by the time cccDNA transcription could be detected and that HBx RNA is present in cell culture-derived virus preparations as well as HBV patient plasma. Collectively, these data indicate that Smc5/6 is an intrinsic antiviral restriction factor that suppresses HBV transcription when localized to ND10 without inducing a detectable innate immune response. Our data also suggest that HBx protein may be initially expressed by delivery of extracellular HBx RNA into HBV-infected cells.

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Section: Discussionmentioning

confidence: 99%

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

et al. 2017

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“…The finding that HBx hijacks Cul4–DDB1 to promote the proteasomal degradation of Smc5/6 was subsequently confirmed by Murphy et al [21] using a different method from Decorsière et al [20]. Briefly, they expressed tagged HBx in HepG2 cells and treated with MLN4924 to inactivate E3-ubiquitin ligase activity.…”

Section: Hbx Promotes the Degradation Of The Structural Maintenancmentioning

confidence: 93%

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

Livingston

Ramakrishnan

Strubin³

et al. 2017

Viruses

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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).

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“…Recently, HBx has been reported to function by recruiting the DDB1 ubiquitin ligase to degrade SMC5/6, a putative negative regulator of HBV transcription (Decorsiere et al, 2016; Murphy et al, 2016). HBx has been reported to also work via AP-2, CREB, TFIIB, TFIH and has also been thought to oppose the cccDNA repressive activities of host protein Spindlin 1 and possibly to “overcome” SETDB1 mediated H3Kme3 and HP1 condensation of cccDNA (Riviere et al, 2015).…”

Section: Transcription Of Cccdna and Transport Of Rna Out Of The Nucleusmentioning

confidence: 99%

“…Exploiting the ability of SMC5/6 to repress HBV cccDNA, is certainly worth exploring, possibly by way of inhibiting the HBx poly-peptide, since HBx was reported to oppose the SMC5/6-mediated repression of HBV cccDNA (Decorsiere et al, 2016; Murphy et al, 2016). …”

Section: Transcription Of Cccdna and Transport Of Rna Out Of The Nucleusmentioning

confidence: 99%

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

et al. 2018

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Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus’ life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions.

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Hepatitis B Virus X Protein Promotes Degradation of SMC5/6 to Enhance HBV Replication

Cited by 257 publications

References 38 publications

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

The Smc5/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection

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

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

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