An antiviral response directed by PKR phosphorylation of the RNA helicase A.
An antiviral response directed by PKR phosphorylation of the RNA helicase A.
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DOI：
10.1371/journal.ppat.1000311
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发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
Williams, Bryan R. G.
中科院分区：
文献类型：
--
作者：
Sadler, Anthony J.;Latchoumanin, Olivier;Hawkes, David;Mak, Johnson;Williams, Bryan R. G.
双链 RNA 激活蛋白激酶 R (PKR) 是先天免疫反应的关键调节因子。病毒感染期间 PKR 的激活最终导致真核翻译起始因子 2 (eIF2α) 的 α 亚基磷酸化，从而抑制蛋白质翻译。 PKR 还具有广泛的监管职能。然而，由于很少有其他 PKR 底物被发现，其机制仍不清楚。此处，PKR 显示与必需的 RNA 解旋酶 RHA 相互作用。此外，RHA 被确定为 PKR 的底物，其磷酸化会扰乱解旋酶与双链 RNA (dsRNA) 的关联。通过这种机制，PKR 可以调节转录，正如其阻止 RHA 催化反式激活反应 (TAR) 介导的 1 型人类免疫缺陷病毒 (HIV-1) 基因调控的能力所揭示的那样。因此，包装在也表达诱饵 RHA 肽的细胞中的 HIV-1 病毒体随后具有增强的感染性。这些数据证明了 dsRNA 代谢关键成分之间的相互作用，既将 RHA 与先天免疫的重要成分联系起来，又描绘了 PKR 在 RNA 代谢中意想不到的作用。我们的手稿通过研究蛋白激酶 PKR 触发的事件来探索对病毒感染的免疫反应。这种前哨激酶在所有细胞中组成型表达为无活性蛋白，随后被感染期间产生的病毒 RNA 激活。活性激酶通过磷酸化细胞中的蛋白质底物来扰乱病毒复制。在这份手稿中，我们确定了 PKR 的一种新底物，一种重要的解旋酶，RHA。病毒利用这种解旋酶来复制自己的基因组。我们证明 PKR 对 RHA 的磷酸化会干扰解旋酶结合病毒 RNA 的能力。相应地，PKR 会阻止 RHA 增强人类免疫缺陷病毒 (HIV) 编码的遗传元件表达的能力。与此相对的是，包装在也表达 RHA 蛋白片段的细胞内的 HIV 病毒颗粒，被证明可以作为诱饵底物与 PKR 相互作用，从而增强了感染性。这些 RHA 片段出现在先前建立的用于结合 RNA 的蛋白质结构域内，但越来越多的人认识到它可以介导蛋白质-蛋白质相互作用。这支持了这些蛋白质结构域在协调细胞对病原体相关 RNA 的反应方面的新作用。这些发现确定了一种新的细胞信号传导途径，对于病毒感染的反应非常重要。
The double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α) to inhibit protein translation. A broad range of regulatory functions has also been attributed to PKR. However, as few additional PKR substrates have been identified, the mechanisms remain unclear. Here, PKR is shown to interact with an essential RNA helicase, RHA. Moreover, RHA is identified as a substrate for PKR, with phosphorylation perturbing the association of the helicase with double-stranded RNA (dsRNA). Through this mechanism, PKR can modulate transcription, as revealed by its ability to prevent the capacity of RHA to catalyze transactivating response (TAR)–mediated type 1 human immunodeficiency virus (HIV-1) gene regulation. Consequently, HIV-1 virions packaged in cells also expressing the decoy RHA peptides subsequently had enhanced infectivity. The data demonstrate interplay between key components of dsRNA metabolism, both connecting RHA to an important component of innate immunity and delineating an unanticipated role for PKR in RNA metabolism. Our manuscript explores the immune response to viral infection by investigating events triggered by the protein kinase PKR. This sentinel kinase is constitutively expressed in all cells as an inactive protein that is subsequently activated by viral RNA produced during an infection. The active kinase perturbs viral replication by phosphorylating protein substrates in the cell. In this manuscript we identify a novel substrate for PKR, an essential helicase, RHA. Viruses usurp this helicase to replicate their own genome. We demonstrate that phosphorylation of RHA by PKR perturbs the ability of the helicase to bind viral RNA. Correspondingly, PKR prevents the capacity of RHA to enhance expression of genetic elements encoded by the human immunodeficiency virus (HIV). Juxtaposed to this, HIV virions packaged within cells that also express protein fragments of RHA, demonstrated to interact with PKR as decoy substrates, have enhanced infectivity. These fragments of RHA occur within a protein domain previously established to bind RNA but increasingly recognized to mediate protein–protein interactions. This supports an emerging role for these protein domains to coordinate the cell's response to pathogen-associated RNA. The findings identify a new cell-signaling pathway important in the response to viral infection.
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影响因子：
64.5
作者：
Dey, M;Cao, C;Dever, TE
通讯作者：
Dever, TE
DOI：
10.1073/pnas.75.12.5893
发表时间：
1978-01-01
影响因子：
11.1
作者：
FARRELL, PJ;SEN, GC;LENGYEL, P
通讯作者：
LENGYEL, P
DOI：
10.1073/pnas.82.13.4341
发表时间：
1985-01-01
影响因子：
11.1
作者：
LAURENT, AG;KRUST, B;HOVANESSIAN, AG
通讯作者：
HOVANESSIAN, AG
影响因子：
7.2
作者：
Gil, J;Esteban, M
通讯作者：
Esteban, M
影响因子：
11.4
作者：
Isken, O;Grassmann, CW;Behrens, SE
通讯作者：
Behrens, SE