Id-1 Induces Proteasome-dependent Degradation of the HBX Protein

Ling, Ming-Tat; Chiu, Yung-Tuen; Lee, Terence; Leung, S.H.; Fung, Maggie K.L.; Wang, Xianghong; Wong, Kwong Fai; Wong, Yi‐Lee

doi:10.1016/j.jmb.2007.06.020

Cited by 30 publications

(27 citation statements)

References 36 publications

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“…The Makorin ring finger protein 1 (MKRN1), the ubiquitin ligase of hTERT, p21, and p53, was able to ubiquitylate and degrade the West Nile virus capsid protein (WNVCp) in a proteasome-dependent manner, protect cells against WNV-induced cell death, and inhibit WNV replication (24). During HBV replication, host factors could facilitate HBx degradation via the ubiquitin-proteasome pathway and thereby inhibit HBV replication (23,27). In our study, cIAP2 promoted HBV polymerase ubiquitylation and degradation and prevented HBV replication in an E3 ligase-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Wang

et al. 2011

J Virol

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Cellular inhibitor of apoptosis protein 2 (cIAP2) is a potent suppressor of apoptotic cell death. We have shown previously that cIAP2 is involved in the tumor necrosis factor alpha (TNF-␣)-induced anti-hepatitis B virus (HBV) response; however, the mechanism for this antiviral effect remains unclear. In the present study, we demonstrate that cIAP2 can significantly reduce the levels of HBV DNA replication intermediates but not the total viral RNA or core protein levels. Domain-mapping analysis revealed that the carboxy-terminal domains of cIAP2 were indispensable for this anti-HBV ability and that an E3 ligase-deficient mutant of cIAP2 (termed cIAP2*) completely lost its antiviral activity. We further identified HBV polymerase as the target of cIAP2. Overexpression of cIAP2 but not cIAP2* reduced polymerase protein levels, while cIAP2 knockdown increased polymerase expression. In addition, we observed that cIAP2 promoted the degradation of the viral polymerase through a proteasome-dependent pathway. Further experiments demonstrated that cIAP2 can bind to polymerase and promote its polyubiquitylation. Finally, we found that cIAP2 downregulated the encapsidation of HBV pregenomic RNA. Taken together, these data reveal a novel mechanism for the inhibition of HBV replication by cIAP2 via acceleration of the ubiquitin-proteasome-mediated decay of polymerase and reduction of the encapsidation of HBV pregenomic RNA, making this mechanism a novel strategy for HBV therapy.Infection with hepatitis B virus (HBV) is a public health problem worldwide. It is estimated that at least 10% of the population of tropical Africa and Far East Asia are chronic carriers of the virus (40). Epidemiological studies have estimated that 350 million people are chronic carriers of HBV, with the potential to develop chronic active hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC) (9). HBV is a small double-stranded DNA virus belonging to the family Hepadnaviridae and replicates primarily in hepatocytes. In the nuclei of hepatocytes, the covalently closed circular DNA (cccDNA) of HBV serves as the transcription template for the viral pregenomic RNA (pgRNA) and subgenomic RNAs. The pgRNA is a multifunctional transcript. This transcript encodes the viral polymerase and core protein while also functioning as the template for HBV reverse transcription. HBV genome replication is initiated upon the recognition and binding of pgRNA by the viral polymerase protein. The complex formed by pgRNA and polymerase is then packaged into nucleocapsids, and in the nucleocapsids, polymerase catalyzes the conversion of pgRNA into single-stranded DNA (ssDNA) and relaxed circular DNA (rcDNA). The mature nucleocapsids are then enveloped and secreted (37).

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Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Wang

et al. 2011

J Virol

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“…The procedures for determination of protein half-life were as described previously [39]. Cells were treated with 1 nM R1881 and collected after treatment with protein synthesis inhibitor cycloheximide (50 ug/ml) for the indicated time point.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of ATM/ATR DNA Damage Checkpoint Promotes Androgen Induced Chromosomal Instability in Prostate Epithelial Cells

et al. 2012

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The ATM/ATR DNA damage checkpoint functions in the maintenance of genetic stability and some missense variants of the ATM gene have been shown to confer a moderate increased risk of prostate cancer. However, whether inactivation of this checkpoint contributes directly to prostate specific cancer predisposition is still unknown. Here, we show that exposure of non-malignant prostate epithelial cells (HPr-1AR) to androgen led to activation of the ATM/ATR DNA damage response and induction of cellular senescence. Notably, knockdown of the ATM gene expression in HPr-1AR cells can promote androgen-induced TMPRSS2: ERG rearrangement, a prostate-specific chromosome translocation frequently found in prostate cancer cells. Intriguingly, unlike the non-malignant prostate epithelial cells, the ATM/ATR DNA damage checkpoint appears to be defective in prostate cancer cells, since androgen treatment only induced a partial activation of the DNA damage response. This mechanism appears to preserve androgen induced autophosphorylation of ATM and phosphorylation of H2AX, lesion processing and repair pathway yet restrain ATM/CHK1/CHK2 and p53 signaling pathway. Our findings demonstrate that ATM/ATR inactivation is a crucial step in promoting androgen-induced genomic instability and prostate carcinogenesis.

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“…Transcription factor E2F1 Co-IP [131] MAVS Mitochondrial anti-viral-signaling protein Co-IP [132] POLR2E DNA-directed RNA polymerase II subunit E Co-IP [133] c-FLIP Cellular FLICE-like inhibitory protein Co-IP [89] TSPX X-chromosome homolog of TSPY Co-IP [64] Id-1 DNA-binding protein inhibitor ID-1 Co-IP [67] STAMP2 Six-transmembrane protein of prostate 2 Co-IP [68] DNMT3A DNA (cytosine-5)-methyltransferase 3A Co-IP…”

Section: E2f1mentioning

confidence: 99%

“…Moreover, p53 reduces the stability of HBx via its downstream target Mouse double minute 2 homolog (MDM2), which binds to HBx and promotes its degradation through an ubiqutinindependent proteasome way [65]. Id-1 is a member of the HLH protein family [66], which interacts with HBx and recruits it to proteasome for degradation [67]. Six transmembrane protein of prostate 2 (STAMP2), also known as TNF-induced adiposerelated protein, was reported to have a direct interaction with HBx examined by Co-IP and immunofluorescence.…”

Section: Influence Of Hbx Interactions On Protein Degradationmentioning

confidence: 99%

Using proteomics to identify the HBx interactome in hepatitis B virus: how can this inform the clinic?

Xie

Chen

Zhang

et al. 2013

Expert Review of Proteomics

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Hepatitis B virus (HBV) is a small and enveloped DNA virus, of which chronic infection is the main risk factor of liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus X protein (HBx) is a multifunctional protein encoded by HBV genome, which have significant effects on HBV replication and pathogenesis. Through directly interacting with cellular proteins, HBx is capable to promote HBV replication, regulate transcription of host genes, disrupt protein degradation, modulate signaling pathway, manipulate cell death and deregulate cell cycle. In this review, we briefly discuss the diversified effects of HBx-interactome and their potential clinical significances.

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Id-1 Induces Proteasome-dependent Degradation of the HBX Protein

Cited by 30 publications

References 36 publications

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Inactivation of ATM/ATR DNA Damage Checkpoint Promotes Androgen Induced Chromosomal Instability in Prostate Epithelial Cells

Using proteomics to identify the HBx interactome in hepatitis B virus: how can this inform the clinic?

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