Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing
Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing
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DOI：
10.1038/s41594-020-0427-3
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发表时间：
2020-05-25
影响因子：
16.8
通讯作者：
Kim, V. Narry
中科院分区：
文献类型：
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作者：
Kim, Dongwan;Lee, Young-suk;Kim, V. Narry
乙型肝炎病毒和人巨细胞病毒转录本通过一个共同的RNA元件募集TENT4-ZCCHC14复合体的混合尾迹保护病毒RNA免受降解。TENT4酶通过非模板化的核苷酸添加在rna的3 '端产生不同核苷酸的“混合尾巴”，以保护信使rna免受死基化。在这里，我们发现乙型肝炎病毒（HBV）和人类巨细胞病毒（HCMV）的转录本中存在广泛的混合尾尾，它们是通过利用TENT4-ZCCHC14复合体的类似机制产生的。HBV和HCMV rna的TAIL-seq显示，TENT4A和TENT4B负责病毒多聚(A)尾的混合尾和保护。我们发现HBV转录后调控元件（PRE），特别是cnggn型五环，对tent4依赖性调控至关重要。HCMV使用类似的五循环，这是趋同进化的一个有趣例子。这个五环被含有无菌α基序结构域的ZCCHC14蛋白识别，该蛋白反过来招募TENT4。总的来说，我们的研究揭示了PRE的作用机制，它已被广泛用于增强基因表达，并确定了TENT4-ZCCHC14复合物作为抗病毒治疗的潜在靶点。
Mixed tailing of hepatitis B virus and human cytomegalovirus transcripts via recruitment of the TENT4-ZCCHC14 complex by a common RNA element protects viral RNAs from degradation.TENT4 enzymes generate 'mixed tails' of diverse nucleotides at 3 ' ends of RNAs via nontemplated nucleotide addition to protect messenger RNAs from deadenylation. Here we discover extensive mixed tailing in transcripts of hepatitis B virus (HBV) and human cytomegalovirus (HCMV), generated via a similar mechanism exploiting the TENT4-ZCCHC14 complex. TAIL-seq on HBV and HCMV RNAs revealed that TENT4A and TENT4B are responsible for mixed tailing and protection of viral poly(A) tails. We find that the HBV post-transcriptional regulatory element (PRE), specifically the CNGGN-type pentaloop, is critical for TENT4-dependent regulation. HCMV uses a similar pentaloop, an interesting example of convergent evolution. This pentaloop is recognized by the sterile alpha motif domain-containing ZCCHC14 protein, which in turn recruits TENT4. Overall, our study reveals the mechanism of action of PRE, which has been widely used to enhance gene expression, and identifies the TENT4-ZCCHC14 complex as a potential target for antiviral therapeutics.