The HBx oncoprotein of hepatitis B virus engages nucleophosmin to promote rDNA transcription and cellular proliferation
The HBx oncoprotein of hepatitis B virus engages nucleophosmin to promote rDNA transcription and cellular proliferation
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DOI：
10.1016/j.bbamcr.2015.04.012
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发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Kumar, Vijay
中科院分区：
文献类型：
--
作者：
Ahuja, Richa;Kapoor, Neetu Rohit;Kumar, Vijay
众所周知，B型肝炎病毒的多效性HBx癌蛋白促进核糖体RNA和已知支持肝细胞癌（HCC）的发展和进展的几种宿主蛋白的表达。尽管核仁磷蛋白（nucleophosmin，NPM）的过度表达与HCC进展相关，但病毒HBx对其的上调及其对核仁功能扰动的影响仍然是个谜。目前的研究表明，HBx上调NPM水平，并劫持其功能，以促进细胞增殖。我们发现HBx表达通过翻译后修饰稳定NPM。在HBx表达时，CDK 2介导的Thr（199）NPM磷酸化增强阻止了其蛋白水解切割，并提供了对凋亡的抗性。此外，HBx直接与NPM的C-末端结构域相互作用，并易位到核仁中，在那里它促进了RNA聚合酶I转录机器到rDNA启动子上的募集。我们的研究结果表明，HBx通过一种新的调节机制，涉及NPM的乙酰化和随后的组蛋白从rDNA启动子耗尽增强rDNA转录。由HBx和NPM共表达引起的核糖体RNA产生的增强促进核糖体生物合成、细胞增殖和转化。总之，我们的研究强烈表明，NPM在介导HBx的致癌作用和相应的核仁扰动诱导的这种病毒癌蛋白的重要作用。(C)2015 Elsevier B. V.版权所有。
The pleiotropic HBx oncoprotein of hepatitis B virus is well known to promote the expression of ribosomal RNAs and several host proteins that are known to support the development and progression of hepatocellular carcinoma (HCC). While overexpression of the nucleolar phosphoprotein, nucleophosmin (NPM), correlates with HCC progression, its upregulation by viral HBx and the resulting impact on perturbed nucleolar functions remain enigmatic. The present study shows that HBx up-regulates NPM levels and hijacks its functions to promote cellular proliferation. We found that HBx expression stabilizes NPM through post-translational modifications. Enhanced CDK2-mediated phosphorylation of NPM at Thr(199) upon HBx expression prevented its proteolytic cleavage and provided resistance to apoptosis. Further, HBx directly interacted with the C-terminal domain of NPM and got translocated into the nucleolus where it facilitated the recruitment of RNA polymerase I transcriptional machinery onto the rDNA promoter. Our results indicate that HBx enhances rDNA transcription via a novel regulatory mechanism involving acetylation of NPM and the subsequent depletion of histones from the rDNA promoter. Enhanced production of ribosomal RNA resulting from co-expression of HBx and NPM promoted ribosome biogenesis, cellular proliferation and transformation. Taken together, our study strongly suggests an important role of NPM in mediating the oncogenic effects of HBx and the corresponding nucleolar perturbations induced by this viral oncoprotein. (C) 2015 Elsevier B.V. All rights reserved.