Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
RNA. 2019 May;25(5):539-556. doi: 10.1261/rna.070169.118. Epub 2019 Feb 15.
The interferon-inducible protein kinase R (PKR) is a key component of host innate immunity that restricts viral replication and propagation. As one of the four eIF2α kinases that sense diverse stresses and direct the integrated stress response (ISR) crucial for cell survival and proliferation, PKR's versatile roles extend well beyond antiviral defense. Targeted by numerous host and viral regulators made of RNA and proteins, PKR is subject to multiple layers of endogenous control and external manipulation, driving its rapid evolution. These versatile regulators include not only the canonical double-stranded RNA (dsRNA) that activates the kinase activity of PKR, but also highly structured viral, host, and artificial RNAs that exert a full spectrum of effects. In this review, we discuss our deepening understanding of the allosteric mechanism that connects the regulatory and effector domains of PKR, with an emphasis on diverse structured RNA regulators in comparison to their protein counterparts. Through this analysis, we conclude that much of the mechanistic details that underlie this RNA-regulated kinase await structural and functional elucidation, upon which we can then describe a "PKR code," a set of structural and chemical features of RNA that are both descriptive and predictive for their effects on PKR.
干扰素诱导蛋白激酶 R（PKR）是宿主固有免疫的关键组成部分，可限制病毒的复制和传播。作为感应多种应激并指导对细胞存活和增殖至关重要的整合应激反应（ISR）的四种 eIF2α 激酶之一，PKR 的多功能作用远远超出了抗病毒防御。由于受到由 RNA 和蛋白质组成的大量宿主和病毒调节剂的靶向作用，PKR 受到多层次的内源性控制和外部操纵，从而推动了其快速进化。这些多功能调节剂不仅包括激活 PKR 激酶活性的典型双链 RNA（dsRNA），还包括具有广泛影响的高度结构化的病毒、宿主和人工 RNA。在这篇综述中，我们讨论了我们对连接 PKR 调节和效应结构域的变构机制的深入理解，重点介绍了与蛋白质对应物相比，各种结构 RNA 调节剂。通过这种分析，我们得出结论，在我们能够描述“PKR 密码”（一套描述性和预测性的 RNA 结构和化学特征，用于描述它们对 PKR 的影响）之前，该 RNA 调控激酶的许多机制细节都有待于结构和功能阐明。
