miR-122 does not impact recognition of the HCV genome by innate sensors of RNA but rather protects the 5' end from the cellular pyrophosphatases, DOM3Z and DUSP11.
miR-122 does not impact recognition of the HCV genome by innate sensors of RNA but rather protects the 5' end from the cellular pyrophosphatases, DOM3Z and DUSP11.
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DOI：
10.1093/nar/gky273
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发表时间：
2018-06-01
影响因子：
14.9
通讯作者：
Sagan SM
中科院分区：
文献类型：
--
作者：
Amador-Cañizares Y;Bernier A;Wilson JA;Sagan SM
丙型肝炎病毒（HCV）将两个肝脏特异性microRNA-122（miR-122）分子募集到其基因组的5′端。这种相互作用促进了病毒RNA的积累，但确切的机制仍不完全清楚。先前的研究表明，miR-122能够保护HCV基因组免受5′核酸外切酶（Xrn 1/2）的影响，但这种保护作用不足以解释miR-122对HCV RNA积累的影响。因此，我们研究了miR-122是否也能够保护病毒基因组免受RNA或细胞焦磷酸酶的先天传感器的影响。我们发现miR-122对PKR、RIG-I样受体或IFIT 1和5的识别没有保护作用。然而，我们发现细胞焦磷酸酶DOM 3 Z和DUSP 11的敲低能够在不存在miR-122的情况下拯救亚基因组复制子的病毒RNA积累。尽管如此，在miR-122敲除的细胞中，焦磷酸酶敲除增加了全长HCV RNA的病毒RNA积累，但没有恢复病毒RNA积累，这表明miR-122可能在HCV生命周期中发挥额外的作用，超出5′端保护。总体而言，我们的结果支持一个模型，其中miR-122通过屏蔽其5′末端免受细胞焦磷酸酶活性和随后的核酸外切酶（Xrn 1/2）的周转来稳定HCV基因组。
Hepatitis C virus (HCV) recruits two molecules of the liver-specific microRNA-122 (miR-122) to the 5′ end of its genome. This interaction promotes viral RNA accumulation, but the precise mechanism(s) remain incompletely understood. Previous studies suggest that miR-122 is able to protect the HCV genome from 5′ exonucleases (Xrn1/2), but this protection is not sufficient to account for the effect of miR-122 on HCV RNA accumulation. Thus, we investigated whether miR-122 was also able to protect the viral genome from innate sensors of RNA or cellular pyrophosphatases. We found that miR-122 does not play a protective role against recognition by PKR, RIG-I-like receptors, or IFITs 1 and 5. However, we found that knockdown of both the cellular pyrophosphatases, DOM3Z and DUSP11, was able to rescue viral RNA accumulation of subgenomic replicons in the absence of miR-122. Nevertheless, pyrophosphatase knockdown increased but did not restore viral RNA accumulation of full-length HCV RNA in miR-122 knockout cells, suggesting that miR-122 likely plays an additional role(s) in the HCV life cycle, beyond 5′ end protection. Overall, our results support a model in which miR-122 stabilizes the HCV genome by shielding its 5′ terminus from cellular pyrophosphatase activity and subsequent turnover by exonucleases (Xrn1/2).
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