Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain
Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain
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DOI：
10.1073/pnas.0409853102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Malik, HS
中科院分区：
文献类型：
--
作者：
Sawyer, SL;Wu, LI;Malik, HS
灵长类基因组编码各种先天免疫策略来保护自己免受逆转录病毒的侵害。其中之一，TRIM 5 α，可以以物种特异性方式限制多种逆转录病毒。因此，尽管恒河猴TRIM 5 α可以强烈限制HIV-1，但人类TRIM 5 α仅具有弱的HIV-1限制。TRIMSalpha限制的生物学表明，它被锁定在与编码病毒衣壳的蛋白质的拮抗冲突中。这种拮抗性相互作用经常导致蛋白质-蛋白质界面处的快速氨基酸替换，因为每个遗传实体都在争夺进化优势。通过分析其进化历史，我们发现了灵长类TRIM 5 α基因中古老的正选择的强有力证据。这种选择是惊人的变化，一些最强的选择发生在人类谱系中。这一历史表明，TRIM 5 α进化是由与多种病毒和内源性逆转录病毒的拮抗相互作用驱动的，这些病毒和内源性逆转录病毒早于灵长类慢病毒的起源。SPRY蛋白结构域中的13个氨基酸的“补丁”具有密集浓度的正选择残基，可能暗示其为抗病毒界面。通过使用嵌合TRIM 5alpha基因的功能研究，我们表明，这个补丁通常是必要的逆转录病毒限制，并负责大多数物种特异性抗逆转录病毒限制活性。我们的研究强调了进化分析的力量，其中积极选择不仅确定了遗传冲突的年龄，而且确定了这种冲突发挥作用的相互作用界面。
Primate genomes encode a variety of innate immune strategies to defend themselves against retroviruses. one of these, TRIM5alpha, can restrict diverse retroviruses in a species-specific manner. Thus, whereas rhesus TRIM5alpha can strongly restrict HIV-1, human TRIM5alpha only has weak HIV-1 restriction. The biology of TRIMSalpha restriction suggests that it is locked in an antagonistic conflict with the proteins encoding the viral capsid. Such antagonistic interactions frequently result in rapid amino acid replacements at the protein-protein interface, as each genetic entity vies for evolutionary dominance. By analyzing its evolutionary history, we find strong evidence for ancient positive selection in the primate TRIM5alpha gene. This selection is strikingly variable with some of the strongest selection occurring in the human lineage. This history suggests that TRIM5alpha evolution has been driven by antagonistic interactions with a wide variety of viruses and endogenous retroviruses that predate the origin of primate lentiviruses. A 13-aa "patch" in the SPRY protein domain bears a dense concentration of positively selected residues, potentially implicating it as an antiviral interface. By using functional studies of chimeric TRIM5alpha genes, we show that this patch is generally essential for retroviral restriction and is responsible for most of the species-specific antiretroviral restriction activity. Our study highlights the power of evolutionary analyses, in which positive selection identifies not only the age of genetic conflict but also the interaction interface where this conflict plays out.