A Role for Fkbp6 and the Chaperone Machinery in piRNA Amplification and Transposon Silencing
A Role for Fkbp6 and the Chaperone Machinery in piRNA Amplification and Transposon Silencing
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DOI：
10.1016/j.molcel.2012.07.019
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发表时间：
2012-09-28
期刊：
影响因子：
16
通讯作者：
Pillai, Ramesh S.
中科院分区：
文献类型：
--
作者：
Xiol, Jordi;Cora, Elisa;Pillai, Ramesh S.
Piwi相互作用RNA（piRNA）对转座子的表观遗传沉默构成了基于RNA的基因组防御机制。Piwi核酸内切酶作用通过由靶转录物通过一种知之甚少的机制产生新的piRNA来扩增皮尔纳池。在这里，我们将小鼠Fkbp6鉴定为将piRNA递送至Piwi蛋白Miwi2的生物合成途径中的因子。缺乏Fkbp6的小鼠抑制LINE1（L1）逆转录转座子，并显示由于Miwi2的核积累不足而减少的DNA甲基化。与其他共伴侣一样，Fkbp6通过其四肽重复（TPR）结构域与分子伴侣Hsp90结合。在昆虫细胞培养模型中抑制ATP依赖性Hsp90活性导致短反义RNA在Piwi复合物中积累。我们确定这些是皮尔纳扩增的副产物，仅在nuage定位的Piwi蛋白中积累。我们认为，伴侣机制通常会抑制这些抑制性RNA，允许Piwi复合物的周转，使其继续参与皮尔纳扩增。
Epigenetic silencing of transposons by Piwi-interacting RNAs (piRNAs) constitutes an RNA-based genome defense mechanism. Piwi endonuclease action amplifies the piRNA pool by generating new piRNAs from target transcripts by a poorly understood mechanism. Here, we identified mouse Fkbp6 as a factor in this biogenesis pathway delivering piRNAs to the Piwi protein Miwi2. Mice lacking Fkbp6 derepress LINE1 (L1) retrotransposon and display reduced DNA methylation due to deficient nuclear accumulation of Miwi2. Like other cochaper-ones, Fkbp6 associates with the molecular chaperone Hsp90 via its tetratricopeptide repeat (TPR) domain. Inhibition of the ATP-dependent Hsp90 activity in an insect cell culture model results in the accumulation of short antisense RNAs in Piwi complexes. We identify these to be byproducts of piRNA amplification that accumulate only in nuage-localized Piwi proteins. We propose that the chaperone machinery normally ejects these inhibitory RNAs, allowing turnover of Piwi complexes for their continued participation in piRNA amplification.