Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Front Immunol. 2023 Apr 26;14:1168589. doi: 10.3389/fimmu.2023.1168589. eCollection 2023.
The intracellular restriction factor TRIM5α inhibits endogenous LINE-1 retroelements. It induces innate immune signaling cascades upon sensing of cytoplasmic LINE-1 complexes, thereby underlining its importance for protecting the human genome from harmful retrotransposition events. Here, we show that a frequent SNP within the RING domain of TRIM5α, resulting in the variant H43Y, blocks LINE-1 retrotransposition with higher efficiency compared to TRIM5α WT. Upon sensing of LINE-1 complexes in the cytoplasm, TRIM5α H43Y activates both NF-κB and AP-1 signaling pathways more potently than TRIM5α WT, triggering a strong block of the LINE-1 promoter. Interestingly, the H43Y allele lost its antiviral function suggesting that its enhanced activity against endogenous LINE-1 elements is the driving force behind its maintenance within the population. Thus, our study suggests that the H43Y variant of the restriction factor and sensor TRIM5α persists within the human population since it preserves our genome from uncontrolled LINE-1 retrotransposition with higher efficiency.
细胞内限制因子 TRIM5α 抑制内源性 LINE-1 反转录元件。它在感知细胞质 LINE-1 复合物时诱导先天免疫信号级联反应，从而强调了其保护人类基因组免受有害反转录转座事件的重要性。在这里，我们表明 TRIM5α 的 RING 结构域内的一个常见 SNP，导致变体 H43Y，与 TRIM5α WT 相比，更有效地阻断 LINE-1 反转录转座。在细胞质中感知 LINE-1 复合物后，TRIM5α H43Y 比 TRIM5α WT 更有效地激活 NF-κB 和 AP-1 信号通路，从而强烈阻断 LINE-1 启动子。有趣的是，H43Y 等位基因失去了其抗病毒功能，这表明其对内源性 LINE-1 元件的增强活性是其在人群中得以维持的驱动力。因此，我们的研究表明，限制因子和传感器 TRIM5α 的 H43Y 变体在人类群体中持续存在，因为它以更高的效率保护我们的基因组免受不受控制的 LINE-1 反转录转座。
