Institute of Clinical and Molecular Virology, Friedrich Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Institute of Clinical and Molecular Virology, Friedrich Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17965-17976. doi: 10.1073/pnas.1922366117. Epub 2020 Jul 10.
Mobile genetic elements have significantly shaped our genomic landscape. LINE-1 retroelements are the only autonomously active elements left in the human genome. Since new insertions can have detrimental consequences, cells need to efficiently control LINE-1 retrotransposition. Here, we demonstrate that the intrinsic immune factor TRIM5α senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5α has been shown to efficiently block HIV-1 replication, while human TRIM5α was found to be less active. Surprisingly, we found that both human and rhesus TRIM5α efficiently repress human LINE-1 retrotransposition. TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In line with its postulated role as pattern recognition receptor, we show that TRIM5α also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-κB, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5α, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5α as pattern recognition receptor and shed light on its previously undescribed activity against mobile genetic elements, such as LINE-1, to protect the integrity of our genome.
移动遗传元件极大地影响了我们的基因组景观。长散布核元件 1（LINE-1）是人类基因组中唯一具有自主活性的元件。由于新的插入可能会产生有害的后果，细胞需要有效地控制 LINE-1 反转录转座。在这里，我们证明固有免疫因子 TRIM5α可以感知和限制 LINE-1 反转录元件。以前，恒河猴 TRIM5α 已被证明能够有效地阻止 HIV-1 的复制，而人类 TRIM5α 的活性较低。令人惊讶的是，我们发现人类和恒河猴 TRIM5α 都能有效地抑制人类 LINE-1 的反转录转座。TRIM5α 在细胞质中与 LINE-1 核糖核蛋白复合物相互作用，这对于限制是必不可少的。与它作为模式识别受体的假定作用一致，我们表明 TRIM5α 在与 LINE-1 核糖核蛋白复合物相互作用时也会诱导先天免疫信号。这些信号事件激活转录因子 AP-1 和 NF-κB，导致 LINE-1 启动子活性的下调。总之，我们的研究结果确定 LINE-1 是人类 TRIM5α 的重要靶标，它通过两种不同的机制限制和感知 LINE-1。我们的结果证实了 TRIM5α 作为模式识别受体，并揭示了它以前未知的针对 LINE-1 等移动遗传元件的活性，以保护我们基因组的完整性。
