Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins.
Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins.
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DOI：
10.1371/journal.ppat.1006066
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发表时间：
2016-12
期刊：
影响因子：
6.7
通讯作者：
Sawyer SL
中科院分区：
文献类型：
--
作者：
Stabell AC;Hawkins J;Li M;Gao X;David M;Press WH;Sawyer SL
Schlafen 11（由SLFN 11基因编码）已被证明可以抑制HIV-1蛋白的积累。我们表明，SLFN 11基因是在猿猴灵长类动物的积极选择，并在其对HIV-1的活性是物种特异性的。人类Schlafen 11的活性相对较弱，与其他灵长类动物的这种蛋白质相比，黑猩猩，猩猩，长颈鹿和绒猴编码的版本是HIV-1蛋白质生产的特别有效的抑制剂。有趣的是，我们发现Schlafen 11在没有感染的情况下是有功能的，并且减少了某些非病毒（GFP）甚至宿主（Escherulin和GAPDH）转录物的蛋白质产生。这表明Schlafen 11可能只是一般性地阻断来自非密码子优化的转录物的蛋白质产生。由于Schlafen 11是一种干扰素刺激的基因，具有广泛的抑制许多宿主和病毒转录物产生蛋白质的能力，因此其作用可能是在细胞中产生一般的抗病毒状态。有趣的是，强抑制剂如绒猴Schlafen 11始终比弱灵长类Schlafen 11蛋白更好地阻断蛋白质的产生，无论分析的病毒或宿主靶点如何。此外，我们表明，Schlafen 11效力图中的物种特异性差异的残基与正选择靶向的残基不同。我们推测，SLFN 11的阳性选择可能是由许多不同的因素驱动的，包括与一种或多种尚未鉴定的病毒拮抗剂的相互作用。Schlafen 11是一种抗HIV-1的人类抗病毒蛋白。在这里，我们发现一些非人类灵长类动物版本的Schlafen 11在阻止病毒蛋白质积累方面比人类Schlafen 11强得多。这些非人灵长类动物Schlafen 11的相对较大的表型使我们能够进一步探索这种蛋白质的机制。我们目前的数据表明，Schlafen 11可能不是一个经典的限制因子，而是一个干扰素刺激的基因，具有广泛的能力，抑制蛋白质的生产，从许多主机和病毒转录，创造一个一般的抗病毒状态的细胞。
Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified. Schlafen11 was recently identified as a human antiviral protein with activity against HIV-1. Here we show that some nonhuman primate versions of Schlafen11 are much stronger at blocking the accumulation of viral proteins than is human Schlafen11. These relatively larger phenotypes of nonhuman primate Schlafen11 allowed us to explore further into the mechanism of this protein. We present data showing that Schlafen11 may not be a classic restriction factor, but rather an interferon-stimulated gene with broad ability to inhibit protein production from many host and viral transcripts, creating a general antiviral state in the cell.
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