A Poxvirus Decapping Enzyme Colocalizes with Mitochondria To Regulate RNA Metabolism and Translation and Promote Viral Replication.
A Poxvirus Decapping Enzyme Colocalizes with Mitochondria To Regulate RNA Metabolism and Translation and Promote Viral Replication.
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去核糖核酸酶去除真核生物的5‘端，导致RNA加速衰退。它们在调节RNA动态平衡方面起着关键作用，并在许多细胞和生命过程中发挥着重要作用。它们编码在许多生物体和病毒中，包括被用作根除天花的疫苗的牛痘病毒。痘苗病毒编码两种解帽酶D9和D10，这两种酶是病毒有效复制和致病所必需的。然而，调控牛痘病毒解毒酶功能的潜在分子机制在很大程度上仍然难以捉摸。在这里，我们证明了牛痘D10几乎完全与线粒体共定位。由于线粒体是高度可移动的细胞器，D10与线粒体的共定位可以在局部聚集D10，并动员它高效地解封mRNAs。在产生病毒转录本的“病毒工厂”中几乎没有观察到线粒体，这表明线粒体共定位提供了一种空间机制，优先去覆盖细胞mRNA而不是病毒mRNA。我们鉴定了D10‘端的三个氨基酸，它们是D10’S线粒体共定位所必需的。线粒体共定位缺失显著抑制了病毒复制，降低了D10‘S在感染过程中去除RNA5’帽的能力，降低了D10‘S基因的表达关闭和促进翻译的能力。
Decapping enzymes remove the 5′ cap of eukaryotic mRNA, leading to accelerated RNA decay. They are critical in regulating RNA homeostasis and play essential roles in many cellular and life processes. They are encoded in many organisms and viruses, including vaccinia virus, which was used as the vaccine to eradicate smallpox. Vaccinia virus encodes two decapping enzymes, D9 and D10, that are necessary for efficient viral replication and pathogenesis. However, the underlying molecular mechanisms regulating vaccinia decapping enzymes’ functions are still largely elusive. Here, we demonstrated that vaccinia D10 almost exclusively colocalized with mitochondria. As mitochondria are highly mobile cellular organelles, colocalization of D10 with mitochondria can concentrate D10 locally and mobilize it to efficiently decap mRNAs. Mitochondria were barely observed in “viral factories,” where viral transcripts are produced, suggesting that mitochondrial colocalization provides a spatial mechanism to preferentially decap cellular mRNAs over viral mRNAs. We identified three amino acids at the N terminus of D10 that are required for D10’s mitochondrial colocalization. Loss of mitochondrial colocalization significantly impaired viral replication, reduced D10’s ability to remove the RNA 5′ cap during infection, and diminished D10’s gene expression shutoff and mRNA translation promotion abilities.
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