SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation.
SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation.
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SAMHD1 通过促进应力颗粒形成来抑制 LINE-1 逆转座。
DOI：
10.1371/journal.pgen.1005367
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发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
Guo F
中科院分区：
文献类型：
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作者：
Hu S;Li J;Xu F;Mei S;Le Duff Y;Yin L;Pang X;Cen S;Jin Q;Liang C;Guo F
SAM结构域和HD结构域包含蛋白1(SAMHD1)抑制逆转录病毒、DNA病毒和长分布元件1(LINE-1)。鉴于在细胞分裂中，SAMHD1失去了其抗病毒功能，但仍然有效地限制了LINE-1，我们建议SAMHD1可能利用不同的机制来控制LINE-1，而不是通过其dNTP三磷水解酶活性来阻止病毒DNA的合成。在这里，我们报道了SAMHD1在促进细胞应激颗粒组装方面的新活性，这与eIF2α的磷酸化增加和eIF4A/eIF4G相互作用的减弱有关。SAMHD1的这一功能增强了LINE-1RNP在应激颗粒中的固存，从而阻断了LINE-1RNP的逆转录转位。为了支持这一新的作用机制，去除应激颗粒标记蛋白G3BP1或TIA1可以消除应激颗粒的形成，并克服SAMHD1对LINE-1的抑制。综上所述，这些数据揭示了SAMHD1通过激活细胞应激颗粒途径控制LINE-1的新机制。长穿插元件1(Line-1或L1)占人类基因组的17%，在塑造人类基因组进化过程中发挥了重要作用。在平均个体基因组中，大约有100个LINE-1拷贝仍然活跃。这些LINE-1序列移动到基因组中的新位置可能会导致零星的疾病病例。在寄主控制LINE-1活性的多层机制中，包括APOBEC3蛋白在内的一组寄主限制因子。SAMHD1因其突变与Aicardi-Goutieres综合征(AGS)有关而闻名，AGS是一种先天性自身免疫性疾病。最近报道SAMHD1是一种宿主限制因子，可以抑制包括人类免疫缺陷病毒1型(HIV-1)和单纯疱疹病毒1型(HSV-1)在内的多种逆转录病毒和DNA病毒。在这里，我们证明了SAMHD1通过促进LINE-1RNP在细胞质应激颗粒中的隔离来抑制LINE-1逆转座。SAMHD1通过诱导eIF2α的磷酸化和破坏eIF4A/eIF4G的相互作用促进大应激颗粒的形成。这是第一个描述SAMHD1在调节应力颗粒形成中的作用的报告。我们认为，SAMHD1的这一功能不仅有助于抑制LINE-1，而且还有助于限制各种病毒。
The SAM domain and HD domain containing protein 1 (SAMHD1) inhibits retroviruses, DNA viruses and long interspersed element 1 (LINE-1). Given that in dividing cells, SAMHD1 loses its antiviral function yet still potently restricts LINE-1, we propose that, instead of blocking viral DNA synthesis by virtue of its dNTP triphosphohydrolase activity, SAMHD1 may exploit a different mechanism to control LINE-1. Here, we report a new activity of SAMHD1 in promoting cellular stress granule assembly, which correlates with increased phosphorylation of eIF2α and diminished eIF4A/eIF4G interaction. This function of SAMHD1 enhances sequestration of LINE-1 RNP in stress granules and consequent blockade to LINE-1 retrotransposition. In support of this new mechanism of action, depletion of stress granule marker proteins G3BP1 or TIA1 abrogates stress granule formation and overcomes SAMHD1 inhibition of LINE-1. Together, these data reveal a new mechanism for SAMHD1 to control LINE-1 by activating cellular stress granule pathway. Long interspersed element 1 (LINE-1 or L1) comprises 17% of human genome, and has played a major role in shaping the evolution of human genome. Approximately 100 copies of LINE-1 are still active in an average individual genome. Movement of these LINE-1 sequences to new loci in the genome has the potential of causing sporadic cases of disease. Among the multi-layered mechanisms by which the host controls LINE-1 activity is a group of host restriction factors including APOBEC3 proteins. SAMHD1 was known for the association of its mutations with the Aicardi-Goutieres syndrome (AGS), a congenital autoimmune disease. SAMHD1 was recently reported as a host restriction factor that inhibits a number of retroviruses and DNA viruses including human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 1 (HSV-1). Here, we demonstrate that SAMHD1 inhibits LINE-1 retrotransposition through promoting the sequestration of LINE-1 RNP within the cytoplasmic stress granules. SAMHD1 promotes the formation of large stress granules by inducing phosphorylation of eIF2α and disrupting eIF4A/eIF4G interaction. This is the first report describing the role of SAMHD1 in modulating the formation of stress granules. We envision that this function of SAMHD1 not only contributes to the inhibition of LINE-1, but also the restriction of various viruses.
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DOI：
10.1146/annurev-genom-082509-141802
发表时间：
2011
影响因子：
8.7
作者：
Beck CR;Garcia-Perez JL;Badge RM;Moran JV
通讯作者：
Moran JV
LINE-1 RNA剪接和对哺乳动物基因表达的影响。
影响因子：
14.9
作者：
Belancio, VP;Hedges, DJ;Deininger, P
通讯作者：
Deininger, P
影响因子：
14.9
作者：
Belancio VP;Roy-Engel AM;Pochampally RR;Deininger P
通讯作者：
Deininger P
影响因子：
3.3
作者：
Arjan-Odedra S;Swanson CM;Sherer NM;Wolinsky SM;Malim MH
通讯作者：
Malim MH
影响因子：
82.9
作者：
通讯作者：
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