TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling.
TRIM5 Retroviral Restriction Activity Correlates with the Ability To Induce Innate Immune Signaling.
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DOI：
10.1128/jvi.02496-15
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Luban J
中科院分区：
文献类型：
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作者：
Lascano J;Uchil PD;Mothes W;Luban J
宿主限制因子TRIM5通过在逆转录完成之前与逆转录病毒衣壳晶格结合并破坏其稳定性，以一种特定的方式抑制逆转录病毒的转导。然而，限制机制可能并不那么简单，因为TRIM5 E3泛素连接酶活性、蛋白酶体、自噬和TAK1依赖的AP-1信号被认为与限制有关。在这里，我们表明，在一个由七个灵长类和食肉动物TRIM5同源基因组成的小组中，每个同源基因都具有潜在的逆转录病毒限制活性，都激活了AP-1信号。相比之下，与TRIM5关系最密切的TRIM家族同源基因则没有。虽然每个灵长类物种都有一个单一的TRIM5基因，但小鼠至少有七个TRIM5同源物，分为两组：Trim12a、-b和-c以及Trim30a、-b、-c和-d。这三种Trim12蛋白激活了先天性免疫信号，而Trim30蛋白则没有，尽管小鼠的TRIM5同源物都没有限制一组克隆的逆转录病毒的任何一组。为了确定是否有任何小鼠TRIM5同源物具有潜在的限制活性，将每个同源物与人类免疫缺陷病毒1型(HIV-1)CA结合蛋白亲环素A(CypA)融合。三个Trim12-CypA融合基因都激活了AP-1并抑制了HIV-1的转导，而Trim30-CypA融合基因两者都没有。TAK1的中断抑制了Trim12-CypA融合对AP-1的激活和对HIV-1的限制。总体而言，这些实验表明，TRIM5逆转录病毒限制活性与激活TAK1依赖的天然免疫信号的能力之间存在很强的相关性。重要性逆转录病毒对敏感宿主生物体进化的重要性怎么估计都不为过。8%的人类基因组是逆转录病毒序列，在过去的感染期间固定在生殖系中。因此，了解后生动物如何保护它们的基因组免受诱变逆转录病毒的感染对生物学具有重要意义。TRIM5是一种细胞蛋白，在将病毒核酸运输到宿主细胞核的过程中，通过破坏逆转录病毒衣壳来保护宿主基因组的完整性。先前的数据表明，先天免疫信号参与了TRIM5介导的限制。在这里，我们证明了先天免疫信号的激活在灵长类和食肉动物的TRIM5同源物之间以及在7个小鼠TRIM5同源物中的3个之间是保守的，并且这种活性是TRIM5介导的限制活性所必需的。
Host restriction factor TRIM5 inhibits retroviral transduction in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. However, the restriction mechanism may not be that simple since TRIM5 E3 ubiquitin ligase activity, the proteasome, autophagy, and TAK1-dependent AP-1 signaling have been suggested to contribute to restriction. Here, we show that, among a panel of seven primate and Carnivora TRIM5 orthologues, each of which has potential for potent retroviral restriction activity, all activated AP-1 signaling. In contrast, TRIM family paralogues most closely related to TRIM5 did not. While each primate species has a single TRIM5 gene, mice have at least seven TRIM5 homologues that cluster into two groups, Trim12a, -b, and -c and Trim30a, -b, -c, and -d. The three Trim12 proteins activated innate immune signaling, while the Trim30 proteins did not, though none of the murine Trim5 homologues restricted any of a panel of cloned retroviruses. To determine if any mouse TRIM5 homologues had potential for restriction activity, each was fused to the human immunodeficiency virus type 1 (HIV-1) CA binding protein cyclophilin A (CypA). The three Trim12-CypA fusions all activated AP-1 and restricted HIV-1 transduction, whereas the Trim30-CypA fusions did neither. AP-1 activation and HIV-1 restriction by the Trim12-CypA fusions were inhibited by disruption of TAK1. Overall then, these experiments demonstrate that there is a strong correlation between TRIM5 retroviral restriction activity and the ability to activate TAK1-dependent innate immune signaling. IMPORTANCE The importance of retroviruses for the evolution of susceptible host organisms cannot be overestimated. Eight percent of the human genome is retrovirus sequence, fixed in the germ line during past infection. Understanding how metazoa protect their genomes from mutagenic retrovirus infection is therefore of fundamental importance to biology. TRIM5 is a cellular protein that protects host genome integrity by disrupting the retroviral capsid as it transports viral nucleic acid to the host cell nucleus. Previous data suggest that innate immune signaling contributes to TRIM5-mediated restriction. Here, we show that activation of innate immune signaling is conserved among primate and carnivore TRIM5 orthologues and among 3 of the 7 mouse Trim5 homologues and that such activity is required for TRIM5-mediated restriction activity.