Yim Howard C H, Wang Die, Yu Liang, White Christine L, Faber Pieter W, Williams Bryan R G, Sadler Anthony J
Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.
Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
Cell Res. 2016 Mar;26(3):367-79. doi: 10.1038/cr.2016.11. Epub 2016 Jan 22.
The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR. We used this animal together with a previously generated transgenic mouse that is ablated for PKR expression to determine the role of PKR in regulating the activity of the cryopyrin inflammasome. Our data demonstrate that, in contradiction to earlier reports, PKR represses cryopyrin inflammasome activity. We demonstrate that this control is mediated through the established function of PKR to inhibit protein translation of constituents of the inflammasome to prevent initial priming during innate immune signaling. These findings identify an important role for PKR to dampen inflammation during the innate immune response and caution against the previously proposed therapeutic strategy to inhibit PKR to treat inflammation.
蛋白激酶R（PKR）通过控制蛋白质翻译和炎症细胞信号通路在抗病毒反应中发挥作用。我们构建了一种转基因敲入小鼠，其内源PKR表达时带有一个使其激酶活性丧失的点突变。这种新型动物使我们能够探究PKR的激酶依赖性和非依赖性功能。我们将这种动物与先前构建的因PKR表达缺失的转基因小鼠一起使用，以确定PKR在调节冷吡啉炎性小体活性中的作用。我们的数据表明，与早期报告相反，PKR抑制冷吡啉炎性小体活性。我们证明这种调控是通过PKR既定的抑制炎性小体成分蛋白质翻译的功能来介导的，以防止在先天免疫信号传导过程中的初始启动。这些发现确定了PKR在先天免疫反应期间抑制炎症的重要作用，并提醒人们警惕先前提出的抑制PKR治疗炎症的治疗策略。
