Institute of Virology and AIDS Research, First Hospital of Jilin University, 519 E. Minzhu Avenue, Changchun, Jilin Province 130061, China.
Cell Rep. 2013 Sep 26;4(6):1108-15. doi: 10.1016/j.celrep.2013.08.019. Epub 2013 Sep 12.
Long interspersed elements 1 (LINE-1) occupy at least 17% of the human genome and are its only active autonomous retrotransposons. However, the host factors that regulate LINE-1 retrotransposition are not fully understood. Here, we demonstrate that the Aicardi-Goutières syndrome gene product SAMHD1, recently revealed to be an inhibitor of HIV/simian immunodeficiency virus (SIV) infectivity and neutralized by the viral Vpx protein, is also a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA retrotransposition. We also found that mutant SAMHD1s of Aicardi-Goutières syndrome patients are defective in LINE-1 inhibition. Several domains of SAMHD1 are critical for LINE-1 regulation. SAMHD1 inhibits LINE-1 retrotransposition in dividing cells. An enzymatic active site mutant SAMHD1 maintained substantial anti-LINE-1 activity. SAMHD1 inhibits ORF2p-mediated LINE-1 reverse transcription in isolated LINE-1 ribonucleoproteins by reducing ORF2p level. Thus, SAMHD1 may be a cellular regulator of LINE-1 activity that is conserved in mammals.
长散在元件 1（LINE-1）占据人类基因组的至少 17%，是其唯一的活跃自主逆转录转座子。然而，调节 LINE-1 逆转录转座的宿主因子尚未完全阐明。在这里，我们证明 Aicardi-Goutières 综合征基因产物 SAMHD1 最近被揭示为 HIV/猿猴免疫缺陷病毒（SIV）感染的抑制剂，并被病毒 Vpx 蛋白中和，也是 LINE-1 和 LINE-1 介导的 Alu/SVA 逆转录转座的有效调节剂。我们还发现 Aicardi-Goutières 综合征患者的突变 SAMHD1 在抑制 LINE-1 方面存在缺陷。SAMHD1 的几个结构域对于 LINE-1 的调节至关重要。SAMHD1 在有丝分裂细胞中抑制 LINE-1 逆转录转座。具有酶活性位点突变的 SAMHD1 保持了对 LINE-1 的显著抑制活性。SAMHD1 通过降低 ORF2p 水平来抑制分离的 LINE-1 核糖核蛋白中 ORF2p 介导的 LINE-1 反转录。因此，SAMHD1 可能是哺乳动物中 LINE-1 活性的细胞调节剂。
