The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
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干扰素刺激的基因编码蛋白 HELZ2 抑制人 LINE-1 逆转录转座和 LINE-1 RNA 介导的 I 型干扰素诱导
DOI：
10.1101/2022.03.26.485892
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Miyoshi Tomoichiro
中科院分区：
文献类型：
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作者：
Luqman-Fatah Ahmad;Watanabe Yuzo;Ishikawa Fuyuki;Moran John V.;Miyoshi Tomoichiro
一些干扰素刺激基因（ISG）编码抑制LINE-1（L1）逆转录转座的蛋白质。在这里，我们使用免疫沉淀，然后液相色谱-串联质谱法，以确定与核糖核蛋白颗粒中的L1 ORF 1编码蛋白（ORF 1 p）相关的蛋白质。三种与ORF 1 p相互作用的ISG蛋白抑制反转录转座：HECT和RLD结构域包含E3泛素蛋白连接酶5（HERC 5）; 2′−5′-寡腺苷酸合成酶样（OASL）;和锌指解旋酶2（HELZ 2）。HERC 5使ORF 1 p不稳定，但不影响其细胞定位。OASL损害ORF 1 p胞质灶形成。HELZ 2识别L1 5′UTR内的序列和/或结构，以降低L1 RNA、ORF 1 p和ORF 1 p胞质病灶水平。WT或逆转录酶缺陷型L1的过表达导致IFN-α表达的适度诱导，其在HELZ 2过表达时被废除。值得注意的是，IFN-α表达在ORF 1 p RNA结合突变体过表达时增强，表明ORF 1 p结合可能保护L1 RNA免受“触发”IFN-α诱导。因此，ISG蛋白可以通过不同的机制抑制反转录转座。
Some interferon stimulated genes (ISGs) encode proteins that inhibit LINE-1 (L1) retrotransposition. Here, we use immunoprecipitation followed by liquid chromatography-tandem mass spectrometry to identify proteins that associate with the L1 ORF1-encoded protein (ORF1p) in ribonucleoprotein particles. Three ISG proteins that interact with ORF1p inhibit retrotransposition: HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5); 2′−5′-oligoadenylate synthetase-like (OASL); and helicase with zinc finger 2 (HELZ2). HERC5 destabilizes ORF1p, but does not affect its cellular localization. OASL impairs ORF1p cytoplasmic foci formation. HELZ2 recognizes sequences and/or structures within the L1 5′UTR to reduce L1 RNA, ORF1p, and ORF1p cytoplasmic foci levels. Overexpression of WT or reverse transcriptase-deficient L1s lead to a modest induction of IFN-α expression, which is abrogated upon HELZ2 overexpression. Notably, IFN-α expression is enhanced upon overexpression of an ORF1p RNA binding mutant, suggesting ORF1p binding might protect L1 RNA from “triggering” IFN-α induction. Thus, ISG proteins can inhibit retrotransposition by different mechanisms.