The alternative cap-binding complex is required for antiviral defense in vivo
The alternative cap-binding complex is required for antiviral defense in vivo
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DOI：
10.1371/journal.ppat.1008155
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发表时间：
2019-12-01
期刊：
影响因子：
6.7
通讯作者：
Pichlmair, Andreas
中科院分区：
文献类型：
--
作者：
Gebhardt, Anna;Bergant, Valter;Pichlmair, Andreas
细胞对环境挑战的反应需要对转录程序进行即时和精确的调控。在病毒感染期间，这包括对抗病原体所必需的抗病毒基因的表达。转录的mRNAs被帽结合复合体(CBC)结合并护送到细胞质中。我们最近发现了一个由NCBP1和NCBP3组成的蛋白质复合体，它在生理条件下对典型的CBC具有冗余功能，由NCBP1和NCBP2组成。在这里，我们提供的证据表明，NCBP3对于建立精确和适当的抗病毒反应是必不可少的。Ncbp3基因缺陷的细胞允许更高的病毒生长，并导致抗病毒反应减弱，这是发生在转录后水平的缺陷。Ncbp3基因缺陷小鼠在甲型流感病毒攻击后出现严重的肺部病变和发病率增加。虽然NCBP3似乎在病毒感染过程中特别重要，但它可能涉及更广泛的内容，以确保适当的蛋白质表达。编码免疫调节和效应蛋白的mRNAs需要运输到细胞质中，以产生对抗病原体所需的蛋白质。在这里，我们表明这一过程需要核帽蛋白3(NCBP3)的适当功能，核帽蛋白3是一种最近被发现有助于替代mRNA帽结合复合体的蛋白质。Ncbp3基因缺陷的小鼠模型在体外允许更高的病毒生长，并在体内表现出对甲型流感病毒攻击的高度敏感性。虽然NCBP3缺失的细胞能够转录上调细胞因子mRNAs，但在没有NCBP3的情况下，细胞因子的生成显著减少。我们的数据表明，NCBP3和替代的帽结合复合体在抗病毒反应中具有非冗余功能。更广泛地说，这项工作展示了转录后基因调控的一个尚未被认识的方面。
Cellular response to environmental challenges requires immediate and precise regulation of transcriptional programs. During viral infections, this includes the expression of antiviral genes that are essential to combat the pathogen. Transcribed mRNAs are bound and escorted to the cytoplasm by the cap-binding complex (CBC). We recently identified a protein complex consisting of NCBP1 and NCBP3 that, under physiological conditions, has redundant function to the canonical CBC, consisting of NCBP1 and NCBP2. Here, we provide evidence that NCBP3 is essential to mount a precise and appropriate antiviral response. Ncbp3-deficient cells allow higher virus growth and elicit a reduced antiviral response, a defect happening on post-transcriptional level. Ncbp3-deficient mice suffered from severe lung pathology and increased morbidity after influenza A virus challenge. While NCBP3 appeared to be particularly important during viral infections, it may be more broadly involved to ensure proper protein expression.Author summary Infection with viruses and other pathogens requires appropriate cellular countermeasures, which involve swift and accurate adaptation of gene expression profiles. mRNAs encoding for immune-regulatory and effector proteins need to be transported into the cytoplasm in order to generate proteins necessary to fight the pathogen. Here we show that this process requires proper functionality of the Nuclear cap protein 3 (NCBP3), a protein recently identified to contribute to an alternative mRNA cap-binding complex. An Ncbp3-deficient mouse model allowed higher virus growth in vitro and showed high susceptibility to influenza A virus challenge in vivo. While NCBP3-deficient cells were able to transcriptionally upregulate cytokine mRNAs, generation of cytokines was significantly reduced in the absence of NCBP3. Our data shows a non-redundant function of NCBP3 and the alternative cap-binding complex in antiviral responses. More broadly, this work demonstrates a yet unappreciated aspect of post-transcriptional gene regulation.