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首頁(yè)> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Hepatocystin/80K-H inhibits replication of hepatitis B virus through interaction with HBx protein in hepatoma cell
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Hepatocystin/80K-H inhibits replication of hepatitis B virus through interaction with HBx protein in hepatoma cell

機(jī)譯：Hepatocystin / 80K-H通過(guò)與肝癌細(xì)胞中HBx蛋白的相互作用抑制乙型肝炎病毒的復(fù)制

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Hepatitis B virus (HBV) X protein (HBx) is a key player in HBV replication as well as HBV-induced hepatocellular carcinoma (HCC). However, the pathogenesis of HBV infection and the mechanisms of host-virus interactions are still elusive. In this study, a combination of affinity purification and mass spectrometry was applied to identify the host factors interacting with HBx in hepatoma cells. Thirteen proteins were identified as HBx binding partners. Among them, we first focused on determining the functional significance of the interaction between HBx and hepatocystin. A physical interaction between HBx and hepatocystin was confirmed by co-immunoprecipitation and Western blotting. Immunocytochemistry demonstrated that HBx and hepatocystin colocalized in the hepatoma cells. Domain mapping of both proteins revealed that the HBx C-terminus (amino acids 110-154) was responsible for binding to the mannose 6-phosphate receptor homology domain (amino acids, 419-525) of hepatocystin. Using translation and proteasome inhibitors, we found that hepatocystin overexpression accelerated HBx degradation via a ubiquitin-independent proteasome pathway. We demonstrated that this effect was mediated by an interaction between both proteins using a HBx deletion mutant. Hepatocystin overexpression significantly inhibited HBV DNA replication and expression of HBs antigen concomitant with HBx degradation. Using the hepatocystin mutant constructs that bind HBx, we also confirmed that hepatocystin inhibited HBx-dependent HBV replication. In conclusion, we demonstrated for the first time that hepatocystin functions as a chaperon-like molecule by accelerating HBx degradation, and thereby inhibits HBV replication. Our results suggest that inducing hepatocystin may provide a novel therapeutic approach to control HBV infection.
機(jī)譯：乙型肝炎病毒（HBV）X蛋白（HBx）是HBV復(fù)制以及HBV誘導(dǎo)的肝細(xì)胞癌（HCC）的關(guān)鍵因素。但是，HBV感染的發(fā)病機(jī)制和宿主病毒相互作用的機(jī)制仍然難以捉摸。在這項(xiàng)研究中，結(jié)合了親和純化和質(zhì)譜技術(shù)來(lái)鑒定與肝癌細(xì)胞中與HBx相互作用的宿主因子。鑒定出13種蛋白質(zhì)為HBx結(jié)合伴侶。其中，我們首先集中于確定HBx和肝素蛋白之間相互作用的功能意義。通過(guò)免疫共沉淀和Western印跡證實(shí)了HBx和肝囊蛋白之間的物理相互作用。免疫細(xì)胞化學(xué)表明，HBx和肝囊蛋白在肝癌細(xì)胞中共定位。兩種蛋白質(zhì)的結(jié)構(gòu)域作圖均顯示HBx C末端（氨基酸110-154）負(fù)責(zé)與肝囊藻毒素的甘露糖6-磷酸受體同源結(jié)構(gòu)域（氨基酸419-525）結(jié)合。使用翻譯和蛋白酶體抑制劑，我們發(fā)現(xiàn)肝囊素過(guò)表達(dá)通過(guò)泛素依賴性蛋白酶體途徑加速了HBx降解。我們證明了這種作用是通過(guò)使用HBx缺失突變體的兩種蛋白質(zhì)之間的相互作用介導(dǎo)的。肝素過(guò)表達(dá)顯著抑制了HBV DNA復(fù)制以及與HBx降解同時(shí)發(fā)生的HBs抗原的表達(dá)。使用結(jié)合HBx的肝囊變突變體構(gòu)建體，我們還證實(shí)了肝囊變抑制了HBx依賴性HBV復(fù)制?？傊覀兪状巫C明了肝素通過(guò)加速HBx降解而起分子伴侶樣分子的作用，從而抑制了HBV復(fù)制。我們的結(jié)果表明，誘導(dǎo)肝囊藻毒素可能提供控制HBV感染的新型治療方法。

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