HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes.
HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes.
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DOI：
10.1371/journal.pone.0166853
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Schmidt WN
中科院分区：
文献类型：
--
作者：
Zhu Z;Tran H;Mathahs MM;Moninger TO;Schmidt WN
端粒酶修复染色体的端粒末端，并且在几乎所有恶性细胞中是活跃的。丙型肝炎病毒（HCV）是已知的致癌和潜在的相互作用与端粒酶系统需要进一步的研究。我们确定了丙型肝炎病毒感染对人端粒酶逆转录酶（TERT）的表达和酶活性在原代人肝细胞和连续细胞系的影响。原代人肝细胞和Huh-7.5肝癌细胞在感染后2-4天表现出早期从头TERT蛋白表达，这些事件与TERT启动子激活、TERT mRNA和端粒酶活性增加同时发生。免疫沉淀研究表明，NS 3 -4A蛋白酶解旋酶，在核心或NS 5A，特异性结合到C-末端区域的TERT通过解旋酶结构域2和蛋白酶序列之间的相互作用。当NS 3 -4A被转染到细胞中时，当加入到TERT和端粒酶RNA的重建混合物中时，以及当与高分子量端粒酶“全酶”复合物一起孵育时，端粒酶活性增加。NS 3 -4A对端粒酶的催化作用被樱草碱或丹诺匹韦抑制，这些药物已知分别抑制NS 3解旋酶和蛋白酶活性。在HCV感染的细胞中，NS 3 -4A可以与端粒酶全酶复合物特异性地回收，而NS 5A或核心蛋白则相反。HCV感染还激活了已知靶向TERT的效应物半胱天冬酶7。活化与TERT的低分子量羧基末端片段的出现相一致，主要大小为45 kD，可以用pancaspase或caspase 7抑制剂抑制。HCV感染诱导TERT表达并刺激端粒酶活性，此外还触发导致增加的TERT降解的半胱天冬酶活性。这些活动表明病毒可以影响瘤形成的多个点。NS 3 -4A蛋白酶解旋酶可以直接结合到端粒酶逆转录酶，增加端粒酶活性，从而潜在地影响端粒修复和宿主细胞的肿瘤行为。
Telomerase repairs the telomeric ends of chromosomes and is active in nearly all malignant cells. Hepatitis C virus (HCV) is known to be oncogenic and potential interactions with the telomerase system require further study. We determined the effects of HCV infection on human telomerase reverse transcriptase (TERT) expression and enzyme activity in primary human hepatocytes and continuous cell lines. Primary human hepatocytes and Huh-7.5 hepatoma cells showed early de novo TERT protein expression 2–4 days after infection and these events coincided with increased TERT promoter activation, TERT mRNA, and telomerase activity. Immunoprecipitation studies demonstrated that NS3-4A protease-helicase, in contrast to core or NS5A, specifically bound to the C-terminal region of TERT through interactions between helicase domain 2 and protease sequences. Increased telomerase activity was noted when NS3-4A was transfected into cells, when added to reconstituted mixtures of TERT and telomerase RNA, and when incubated with high molecular weight telomerase ‘holoenzyme’ complexes. The NS3-4A catalytic effect on telomerase was inhibited with primuline or danoprevir, agents that are known to inhibit NS3 helicase and protease activities respectively. In HCV infected cells, NS3-4A could be specifically recovered with telomerase holoenzyme complexes in contrast to NS5A or core protein. HCV infection also activated the effector caspase 7 which is known to target TERT. Activation coincided with the appearance of lower molecular weight carboxy-terminal fragment(s) of TERT, chiefly sized at 45 kD, which could be inhibited with pancaspase or caspase 7 inhibitors. HCV infection induces TERT expression and stimulates telomerase activity in addition to triggering Caspase activity that leads to increased TERT degradation. These activities suggest multiple points whereby the virus can influence neoplasia. The NS3-4A protease-helicase can directly bind to TERT, increase telomerase activity, and thus potentially influence telomere repair and host cell neoplastic behavior.
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影响因子：
14.9
作者：
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通讯作者：
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