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Hepatitis B virus polymerase suppresses NF-?B signaling by inhibiting the activity of IKKs via interaction with Hsp90?.

ABSTRACT: Nuclear factor-?B (NF-?B) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-? (IFN-?) activity by disrupting the interaction between IKK? and the DDX3. In the current study, we found that HBV Pol suppressed NF-?B signaling, which can also contribute to IFN-? production. HBV Pol did not alter the level of NF-?B expression, but it prevented NF-?B subunits involved in both the canonical and non-canonical NF-?B pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the I?B kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-?B-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-? activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.

SUBMITTER: Liu D

PROVIDER: S-EPMC3950214 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Hepatitis B virus polymerase suppresses NF-κB signaling by inhibiting the activity of IKKs via interaction with Hsp90β.

Liu Dan D Wu An'dong A Cui Lei L Hao Ruidong R Wang Yuan Y He Jing J Guo Deyin D

PloS one 20140311 3

Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of ...[more]

PMID: 24618592

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Project description:Breast cancer metastasis is the primary cause of mortality of patients with breast cancer. The present study aimed to explore the role and underlying mechanisms of IGJ in the invasion and metastasis of breast cancer. The Cancer Genome Atlas database was utilized to analyze the differential gene expression profiles in patients with breast cancer with or without metastasis; the target gene, joining chain of multimeric IgA and IgM (JCHAIN, also known as IGJ, as referred to herein), with significant expression and with prognostic value was screened. The expression levels of IGJ in human breast cancer paired tissues and cell lines were detected using reverse transcription‑quantitative PCR and western blot analysis. IGJ differential expression was detected in paired human breast cancer tissues using immunohistochemistry. The role of IGJ in breast cancer was verified using CCK‑8, invasion and migration assays, and scratch tests in vivo and in vitro. Further exploration of the role and mechanism of IGJ in breast cancer was conducted through Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes analysis, western blot analysis and immunofluorescence experiments. Through the analysis of gene expression profiles, it was found that IGJ was poorly expressed in patients with breast cancer with metastasis compared to patients with non‑metastatic breast cancer. The overexpression of IGJ was associated with an improved distant metastasis‑free survival and overall survival (OS). COX multivariate regression analysis demonstrated that IGJ was an independent prognostic factor for the OS and relapse‑free survival of patients with breast cancer. In comparison to healthy breast cancer adjacent tissues and cell lines, IGJ was poorly expressed in breast cancer tissues and cell lines (P<0.05). Further analyses indicated that the overexpression of IGJ suppressed the proliferation, invasion and metastasis of breast cancer cells in vivo and in vitro by inhibiting the occurrence of epithelial‑to‑mesenchymal transition (EMT) and suppressing the nuclear translocation of p65. Finally, rescue experiments indicated that IGJ restricted the proliferation and metastasis of breast cancer cells by regulating the NF‑κB signaling pathway. On the whole, the present study demonstrates that IGJ suppresses the invasion and metastasis of breast cancer by inhibiting both the occurrence of EMT and the NF‑κB signaling pathway. These findings may provide novel biomarkers and potential therapeutic targets for the treatment of metastatic breast cancer.

Dataset Information

Hepatitis B virus polymerase suppresses NF-?B signaling by inhibiting the activity of IKKs via interaction with Hsp90?.

Publications

Hepatitis B virus polymerase suppresses NF-κB signaling by inhibiting the activity of IKKs via interaction with Hsp90β.

Similar Datasets

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