Host factors that control long terminal repeat retrotransposons in Saccharomyces cerevisiae: implications for regulation of mammalian retroviruses.
Host factors that control long terminal repeat retrotransposons in Saccharomyces cerevisiae: implications for regulation of mammalian retroviruses.
复制标题
控制酿酒酵母中长末端重复逆转录转座子的宿主因素：对哺乳动物逆转录病毒调节的影响。
DOI：
10.1128/ec.00092-07
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Curcio,MJoan
中科院分区：
文献类型：
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作者：
Maxwell,PatrickH;Curcio,MJoan
逆转录病毒包括一组独特的包膜RNA病毒，通过逆转录其RNA基因组在病毒核心颗粒内形成DNA副本进行复制。DNA拷贝（cDNA）随后被整合到宿主基因组中。整合的前病毒DNA被RNA聚合酶II （Pol II）转录，产生多腺苷化的mrna，这些mrna被翻译成病毒蛋白，也被包装成细胞质或质膜上的组装核心颗粒。核心颗粒在脱离细胞时获得宿主衍生的包膜。逆转录病毒粒子的膜与新宿主细胞的膜融合，复制周期再次开始（图1）。逆转录病毒是专性寄生虫，具有小基因组和复杂的复制模式；因此，它们依赖于大量的宿主因子进行复制。与此同时，哺乳动物细胞已经进化出多种机制来阻止逆转录病毒，逆转录病毒对其宿主具有潜在的致病性或诱变性。近年来，在确定调节逆转录病毒活性的哺乳动物宿主因子方面取得了重大进展。许多显性逆转录病毒抗性因子，包括胞嘧啶脱氨酶APOBEC3家族、小鼠Fv1限制性因子和灵长类动物抗病毒因子TRIM5，已经通过遗传学方法被发现（文献7和文献49综述）。此外，通过对生化和双杂交相互作用以及显性阴性突变体的分析，已经确定了在逆转录病毒生命周期的不同步骤中促进复制的多种隐性基因（见文献47和48）。这项工作加深了我们对宿主-逆转录病毒关系复杂性的认识，并说明了宿主和病原体之间复杂的相互作用还有多少有待了解。在这篇综述中，我们探讨了使用一个简单的模式生物来系统地识别参与逆转录病毒复制的宿主因子的功能同源物的价值。鉴定哺乳动物基因是否积极或消极地参与逆转录病毒繁殖的一个简单方法是首先鉴定模式生物中调节逆转录病毒样转座子的基因，然后测试突变或减少相应哺乳动物蛋白表达对逆转录病毒复制的影响。在许多哺乳动物物种中，通过RNA干扰特异性降低单个基因表达的工具的发展大大提高了这种方法的可行性。逆转录病毒样转座子在真核生物中普遍存在，并且在宿主基因组中占很大比例，从出芽酵母酵母基因组的3%到人类基因组的约8%（12,36）。虽然逆转录病毒样转座子不具有致病性，但它们是有效的插入诱变剂。除了病毒颗粒出芽和新细胞感染的明显例外，转位中的许多步骤与逆转录病毒复制的步骤类似（图1）。因此，酿酒葡萄球菌中的Ty1和Ty3逆转录病毒样转座子作为模型被广泛研究，以探索宿主细胞对逆转录病毒繁殖的影响（71,87,106）。稳定的单倍体生长阶段，遗传和基因组学工具的可用性以及生物化学研究的可行性是酿酒酵母的一些特征，这些特征允许快速识别宿主因子并分析它们对逆转录病毒样元素复制的影响。逆转录病毒和逆转录病毒样转座子由末端直接重复序列组成，称为长末端重复序列（LTRs）。
Retroviruses comprise a distinct group of enveloped RNA viruses that replicate by reverse transcribing their RNA genomes to form a DNA copy within a viral core particle. The DNA copy, or cDNA, is then integrated into the host genome. The integrated proviral DNA is transcribed by RNA polymerase II (Pol II) to produce polyadenylated mRNAs that are translated into viral proteins and also packaged into assembling core particles in the cytoplasm or at the plasma membrane. Core particles acquire a host-derived envelope as they bud out of the cell. The membrane of retroviral virions fuses with the membrane of new host cells, and the replication cycle begins again (Fig. 1). Retroviruses are obligate parasites with small genomes and a complex mode of replication; thus, they are reliant on a multitude of host factors for replication. At the same time, mammalian cells have evolved a variety of mechanisms to impede retroviruses, which are potentially pathogenic or mutagenic to their hosts. Significant progress toward identifying mammalian host factors that regulate the activities of retroviruses has been made in recent years. A number of dominant retroviral resistance factors, including the APOBEC3 family of cytosine deaminases, the mouse Fv1 restriction factor, and the primate antiviral factor TRIM5, have been uncovered using genetic approaches (reviewed in references 7 and 49). In addition, a diverse collection of recessive genes that promote replication at a variety of steps in the retroviral life cycle have been identified through the analysis of biochemical and two-hybrid interactions and dominant-negative mutants (reviewed in references 47 and 48). This body of work has deepened our appreciation of the complexity of the host-retrovirus relationship and illustrated how much remains to be understood about the intricate interplay between host and pathogen. In this review, we explore the value of using a simple model organism to systematically identify functional orthologs of host factors involved in retroviral replication. A facile approach to the identification of mammalian genes that participate positively or negatively in retroviral propagation is first to identify genes that regulate retrovirus-like transposons in a model organism and then to test the effect on retroviral replication of mutating or reducing the expression of the corresponding mammalian protein. The development of tools to specifically reduce the expression of individual genes through RNA interference in many mammalian species has dramatically enhanced the feasibility of this approach. Retrovirus-like transposons are ubiquitous in eukaryotes and constitute a significant percentage of the host genome, from 3% of the genome of the budding yeast Saccharomyces cerevisiae to approximately 8% of the human genome (12, 36). While retrovirus-like transposons are not pathogenic, they are potent insertional mutagens. Many of the steps in transposition, with the notable exception of viral-particle budding and infection of new cells, are analogous to steps involved in the replication of retroviruses (Fig. 1). Consequently, the Ty1 and Ty3 retrovirus-like transposons in S. cerevisiae have been studied extensively as models to explore the inffuence of the host cell on retroviral propagation (71, 87, 106). The stable haploid phase of growth, the availability of genetic and genomics tools, and the feasibility of biochemical studies of S. cerevisiae are some of the features that permit rapid identification of host factors and analysis of their effects on the replication of retrovirus-like elements.Retroviruses and retrovirus-like transposons consist of terminal direct-repeat sequences known as long terminal repeats (LTRs …