Hepatitis B Virus X Protein Is Stabilized by the Deubiquitinating Enzyme VCPIP1 in a Ubiquitin-Independent Manner by Recruiting the 26S Proteasome Subunit PSMC3

Wu, Qiong; Zhang, Lu; Xu, Xiaofeng; Zhang, Yi; Shi, Jiajian; Lin, Xu; Chen, Wan-Nan

doi:10.1128/jvi.00611-22

Cited by 5 publications

(4 citation statements)

References 52 publications

(78 reference statements)

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“…For example, TRIM21 inhibited HBV replication through ubiquitin-mediated proteasomal degradation of HBx [ 28 ], and NEDD4 prohibited HBV infection by mediating K48-linked degradation of HBx and inhibiting HBV-associated HCC [ 29 ]. In addition, the deubiquitinating enzyme VCPIP1 binds to HBx protein and promotes stabilization of HBx in a ubiquitin-independent manner by recruiting the PSMC3 in vivo [ 30 ]. Therefore, ubiquitin-mediated or deubiquitin-mediated HBV proteins are a critical regulatory step during HBV infections.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase OTUD5 promotes hepatitis B virus replication by removing K48-linked ubiquitination of HBV core/precore and upregulates HNF4ɑ expressions by inhibiting the ERK1/2/mitogen-activated protein kinase pathway

Lou,

Ma,

et al. 2023

Cell. Mol. Life Sci.

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Hepatitis B virus (HBV) infection is a major public health problem worldwide, causing nearly one million deaths annually. OTUD5 is a deubiquitinase associated with cancer development and innate immunity response. However, the regulatory mechanisms of OTUD5 underlying HBV replication need to be deeply elucidated. In the present investigation, we found that HBV induced significant up-regulation of OTUD5 protein in HBV-infected cells. Further study showed that OTUD5 interacted with HBV core/precore, removing their K48-linked ubiquitination chains and protecting their stability. Meanwhile, overexpression of OTUD5 could inhibit the MAPK pathway and then increase the expression of HNF4ɑ, and ERK1/2 signaling was required for OTUD5-mediated activation of HNF4α, promoting HBV replication. Together, these data indicate that OTUD5 could deubiquitinate HBV core protein degradation by its deubiquitinase function and promote HBV activity by up-regulating HNF4α expression via inhibition of the ERK1/2 pathway. These results might present a novel therapeutic strategy against HBV infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Deubiquitinase OTUD5 promotes hepatitis B virus replication by removing K48-linked ubiquitination of HBV core/precore and upregulates HNF4ɑ expressions by inhibiting the ERK1/2/mitogen-activated protein kinase pathway

Lou,

Ma,

et al. 2023

Cell. Mol. Life Sci.

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show abstract

“…Posttranslational regulation of hepatitis B virus structural proteins had been an important cellular process during HBV infection, for example, TRIM21 inhibited HBV replication through ubiquitin-mediated proteasomal degradation of HBx 28 , NEDD4 prohibited HBV infection by mediating K48-linked degradation of HBx and inhibits HBV-associated HCC 29 . In addition, deubiquitinating enzyme VCPIP1 binds to HBx protein and promotes stabilization of HBx in a ubiquitin-independent manner by recruiting the PSMC3 in vivo 30 . Therefore, ubiquitin-mediated or deubiquitin-mediated HBV protein components is critical regulatory step in HBV-host protein interaction processes.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase OTUD5 Promotes Hepatitis B Virus Replication by Removing K48-linked Ubiquitination of HBV core/precore and Up-regulating HNF4ɑ Expressions through Inhibiting the ERK1/2 /Mitogen-activated Protein Kinase Pathway

Liu

et al. 2023

Preprint

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Hepatitis B virus (HBV) infection is a major public health problem worldwide, causing nearly one million deaths annually. OTUD5 is a deubiquitinase associated with cancer development and innate immunity response. However, the regulatory mechanisms of OTUD5 underlying HBV replication need to be deeply elucidated. In the present investigation, we found that HBV induced significant up-regulation of OTUD5 protein in HBV-infected cells. Further study showed that OTUD5 displayed interaction with HBV core/precore, removing their K48-linked ubiquitination chains, and protecting their stability. Meanwhile, overexpression of OTUD5 could inhibit the MAPK pathway, and then increase the expression of HNF4ɑ, and ERK1/2 signaling was required for OTUD5-mediated activation of HNF4α, resulting in the promotion of HBV replication. Together, these data indicate that OTUD5 could inhibit HBV core protein degradation by its deubiquitinase function and promote HBV activity by up-regulating HNF4α expression via inhibition of ERK1/2 pathway. These results might present as a novel therapeutic strategy against HBV infection.

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“…HBx turnover can be processed by both ubiquitin-dependent and ubiquitin-independent proteasomal steps [37]. To verify the underlying mechanism of the enhanced HBx stability in rt269L-infection, we performed a ubiquitination assay by detecting the ubiquitination of HBx proteins with immunoprecipitation.…”

Section: Rt269l Attenuates Hbx Degradation Through Ubiquitination Of Hbxmentioning

confidence: 99%

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

et al. 2023

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Background In our previous report, the rt269I type versus the rt269L type in genotype C2 infection led to poor clinical outcomes and enhanced mitochondrial stress in infected hepatocytes. Here, we sought to investigate differences between the rt269L and rt269I types in mitochondrial functionality in hepatitis B virus (HBV) genotype C2 infection, mainly focusing on endoplasmic reticulum (ER) stress-mediated autophagy induction as an upstream signal. Methods Mitochondrial functionality, ER stress signaling, autophagy induction, and apoptotic cell death between rt269L-type and rt269I-type groups were investigated via in vitro and in vivo experiments. Serum samples were collected from 187 chronic hepatitis patients who visited Konkuk or Seoul National University Hospital. Results Our data revealed that genotype C rt269L versus rt269I infection led to improved mitochondrial dynamics and enhanced autophagic flux, mainly due to the activation of the PERK–eIF2α–ATF4 axis. Furthermore, we demonstrated that the traits found in genotype C rt269L infection were mainly due to increased stability of the HBx protein after deubiquitination. In addition, clinical data using patient sera from two independent Korean cohorts showed that, compared with rt269I, rt269L in infection led to lower 8-OHdG levels, further supporting its improved mitochondrial quality control. Conclusion Our data showed that, compared with the rt269I type, the rt269L type, which presented exclusively in HBV genotype C infection, leads to improved mitochondrial dynamics or bioenergetics, mainly due to autophagy induction via activation of the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner. This suggests that HBx stability and cellular quality control in the rt269L type predominating in genotype C endemic areas could at least partly contribute to some distinctive traits of genotype C infection, such as higher infectivity or longer duration of the hepatitis B e antigen (HBeAg) positive stage. Graphical Abstract

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Hepatitis B Virus X Protein Is Stabilized by the Deubiquitinating Enzyme VCPIP1 in a Ubiquitin-Independent Manner by Recruiting the 26S Proteasome Subunit PSMC3

Abstract: HBx is a multifunctional viral oncoprotein that plays an essential role in the viral life cycle and hepatocarcinogenesis. HBx degradation occurs through the ubiquitin-proteasome system (UPS).

Cited by 5 publications

References 52 publications

Deubiquitinase OTUD5 promotes hepatitis B virus replication by removing K48-linked ubiquitination of HBV core/precore and upregulates HNF4ɑ expressions by inhibiting the ERK1/2/mitogen-activated protein kinase pathway

Deubiquitinase OTUD5 promotes hepatitis B virus replication by removing K48-linked ubiquitination of HBV core/precore and upregulates HNF4ɑ expressions by inhibiting the ERK1/2/mitogen-activated protein kinase pathway

Deubiquitinase OTUD5 Promotes Hepatitis B Virus Replication by Removing K48-linked Ubiquitination of HBV core/precore and Up-regulating HNF4ɑ Expressions through Inhibiting the ERK1/2 /Mitogen-activated Protein Kinase Pathway

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

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