E3 ubiquitin ligase TRIM21 restricts hepatitis B virus replication by targeting HBx for proteasomal degradation

Song, Yahui; Li, Min; Wang, Yanqi; Zhang, Hongkai; Lin, Wei; Xu, Wei

doi:10.1016/j.antiviral.2021.105107

Cited by 30 publications

(34 citation statements)

References 49 publications

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“…The types of ubiquitinating enzymes and DUBs and their direct roles in the process require further investigation. To date, several E3 ubiquitin ligases, e.g., Siah-1 ( 12 ), murine double minute 2 (MDM2) ( 37 ), tripartite motif-containing 21 (TRIM21) ( 38 ), and mitochondrial E3 ubiquitin ligase (MARCH5) ( 39 ), degrade HBx, while USP15 has been identified as a DUB that stabilizes HBx ( 16 ). DUBs cleave ubiquitin molecules from either the E3 ligase or the target proteins, thereby preempting ubiquitin-mediated regulation ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

et al. 2022

J Virol

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Section: Discussionmentioning

confidence: 99%

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

Zhang

et al. 2022

J Virol

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“…Previous studies have reported that NQO1 could regulate the proteasomal degradation of HBx, thereby inhibiting HBV cccDNA activity [ 17 ]. Other studies have reported that intracellular restriction genes, including TRIM21, ISG15, and TRIM31, could eliminate HBx [ 18 , 19 , 20 ]. Another inhibition strategy against HBx could include short hairpin RNAs against HBx [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx

Chen

et al. 2022

Molecules

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HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.

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“…Several types of ubiquitin linkages catalyzed by TRIM21 have been reported, and different ubiquitin linkages play distinct roles in host defense against pathogenic invasion (Jones EL et al, 2021). For instance, TRIM21-mediated K48-linked ubiquitination is tightly related to proteasome-dependent degradation, which results in the degradation of viral proteins in virus-infected cells (Mu T et al, 2020, Song Y et al, 2021, Hauler F et al, 2012). However, K48-linked ubiquitination of DDX41, one of the sensors detecting dsDNA, results in the inhibition of the innate immune response triggered by DNA virus (Zhang Z et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Regulation of protein translation by TRIM21

Liu

et al. 2022

Preprint

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Regulation of translation initiation is essential for maintenance of protein homeostasis and typically involves the phosphorylation of translation initiation factor eIF2? in eukaryotes. In response to stressors, cells employ eIF2α-dependent signaling to control translation initiation. We focus on the role of TRIM21 in the regulation of protein translation mediated by PKR which phosphorylates eIF2α. TRIM21 deficiency enhances PKR activation. TRIM21 interacts with PKR, and the E3 ligase activity of TRIM21 is crucial for stress-triggered PKR inactivation. TRIM21 interacts with the PKR phosphatase PP1α and promotes K6-linked polyubiquitination of PP1α. Ubiquitination of PP1α augments its interaction with PKR, causing PKR inactivation and subsequent dephosphorylation of eIF2α, initiating protein synthesis. Moreover, TRIM21 constitutively restricts viral infection by reversing PKR-mediated inhibition of the protein synthesis of intrinsic antiviral genes. The TRIM21-PP1α axis acts as a newly discovered program that regulates PKR-associated protein synthesis and broadens our knowledge of antiviral genes. Moreover, TRIM21-mediated regulation of PKR activation provides evidence that TRIM21 may anticipate the interferon-dependent immunotherapy. Our study highlights the essential role of TRIM21 in regulating protein translation.

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E3 ubiquitin ligase TRIM21 restricts hepatitis B virus replication by targeting HBx for proteasomal degradation

Cited by 30 publications

References 49 publications

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

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

Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx

Regulation of protein translation by TRIM21

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