乙肝病毒X蛋白调节宿主细胞自吞噬
原贴由bigben发表于 2009-5-8 00:11Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression
Abstract
Human beclin 1 is the first identified mammalian gene to induce autophagy. It is commonly expressed at reduced levels in breast tumors; however, it is overexpressed in hepatitis B virus (HBV)-infected cancerous liver tissues. To expose the possible mechanism and biological significance of this up-regulation of beclin 1, we investigated the regulation of beclin 1 expression by HBV x protein (HBx) in hepatic or hepatoma cell lines. Here, we showed that enforced expression of HBx by transfection technology results in the up-regulation of the endogenous messenger RNA (mRNA) and protein levels of Beclin 1 in the tested cells. Using a luciferase- reporter assay, we demonstrated that HBx transactivates beclin 1 promoter activity in a dose-dependent manner. The promoter region of the beclin 1 gene identified in this study is located at nt -277/+197 and has the maximum transcriptional activity. HBx-mediated up-regulation of beclin 1 expression might be direct, that is, via its promoter. Furthermore, the cells that transiently or stably expressed HBx showed an enhanced accumulation of vacuoles carrying the autophagy marker LC3 as compared with the control cells, which was induced by nutrient starvation, indicating HBx-enhanced autophagy. Moreover, this enhanced autophagy occurred in HepG2.2.15 cells that replicate HBV and in cells transfected with HBV genomic DNA, suggesting that HBV infection also causes increased levels of autophagy under starvation conditions. Treatment of cells with beclin 1 small interfering RNA (siRNA) blocked HBx-enhanced autophagy, demonstrating that the function of HBx in influencing autophagy is Beclin 1 dependent. Conclusion: Our findings suggest a novel function of HBx in increasing autophagy through the up-regulation of beclin1 expression, and this may provide an important mechanism in HBV-infected hepatocytes growing under nutrient-deficient conditions. (HEPATOLOGY 2009;49:60-71)
近期《肝脏学》(Hepatology 2009, Vol. 49, No.1, p60-71)杂志发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所赵慕钧研究组的最新研究发现：即乙型肝炎病毒X蛋白(HBx)调控beclin 1基因表达从而影响饥饿诱导的细胞自吞噬(autophagy)。
乙肝病毒(HBV)感染不仅可引起急、慢性肝炎, 而且与肝硬化、肝癌的发生密切相关。在HBV编码的蛋白中，乙型肝炎病毒X蛋白(HBx)被认为是参与慢性乙型肝炎病理过程和诱发肝癌的最重要的蛋白质。乙肝病毒X蛋白间接调控宿主细胞内许多基因的转录，广泛影响宿主细胞的各种生命活动，包括调节细胞凋亡，抑制细胞DNA的修复，干扰细胞有丝分裂和细胞周期进程等等。
赵慕钧研究组的唐红博士生等多人参与研究，发现了HBx的一个新功能——调节宿主细胞的自吞噬。自吞噬是细胞通过自我降解细胞器和生物大分子等从而产生核苷，氨基酸和脂肪酸的循环利用过程，可以在营养物质缺乏时维持细胞生存。人beclin 1基因是哺乳动物中第一个被发现的诱导自吞噬的基因。该研究组发现beclin 1基因在HBV阳性肝癌组织中表达升高，当他们将HBx导入肝和肝癌细胞发现可以提高细胞内源Beclin 1的表达水平。然后，他们鉴定了beclin 1基因启动子，证明HBx可增强beclin 1启动子活性，提高胞内Beclin 1蛋白质水平。Beclin 1是自吞噬的关键分子之一，它与ClassⅢ PI3K结合形成复合物，促进早期自吞体膜结构的形成。进一步的工作证明HBx通过上调Beclin 1的表达，增强了细胞对饥饿引起的自吞噬的敏感性。在对HBV阳性肝细胞的研究中也发现，HBV感染增强了宿主细胞的自吞噬，而这一作用正是HBx依赖的。上述研究结果提示了HBV感染的肝细胞在饥饿环境下一种可能的生存机制，为研究HBV感染与肝癌发生发展提供了新的思路。
这项工作受到了国家863项目(2006AA02Z190和2002AA711A02)的经费资助。（来源：中国科学院上海生命科学研究院）
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