PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR
PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR
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DOI：
10.1074/jbc.m004762200
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发表时间：
2000-12-01
影响因子：
4.8
通讯作者：
Patel, RC
中科院分区：
文献类型：
--
作者：
Patel, CV;Handy, I;Patel, RC
干扰素（IFN）诱导的双链（ds） rna激活的丝氨酸-苏氨酸蛋白激酶（PKR）是IFN抗病毒活性的关键介质。此外，PKR活性还参与细胞增殖、凋亡和信号转导的调控。在病毒感染的细胞中，dsRNA已被证明结合并激活PKR激酶功能。PKR活性在正常细胞过程中的含义已经调用了除dsRNA以外的激活因子，因为在细胞rna中缺乏具有足够长度的完全双工区域的rna，这些区域能够激活PKR。我们最近报道了一种新的PKR蛋白激活剂PACT的克隆。PACT与PKR异源二聚并通过直接的蛋白-蛋白相互作用激活PKR。哺乳动物细胞中PACT的过表达会导致PKR的细胞底物真核起始因子2 （eIF2 α）的α亚基磷酸化，并导致蛋白质合成抑制。在这里，我们提出的证据表明，内源性PACT作为PKR的蛋白质激活剂，响应不同的应激信号，如血清饥饿、过氧化物或亚砷酸盐处理。在细胞暴露于这些应激因子后，PACT被磷酸化，并以增加的亲和力与PKR结合。pact介导的PKR激活导致eIF2 α磷酸化增强，随后发生细胞凋亡。基于这些结果，我们提出PACT是一种新的应激调节PKR生理激活剂。
The interferon (IFN)-induced, double-stranded (ds)RNA-activated serine-threonine protein kinase, PKR, is a key mediator of the antiviral activities of IFNs. In addition, PKR activity is also involved in regulation of cell proliferation, apoptosis, and signal transduction. In virally infected cells, dsRNA has been shown to bind and activate PKR kinase function. Implication of PKR activity in normal cellular processes has invoked activators other than dsRNA because RNAs with perfectly duplexed regions of sufficient length that are able to activate PKR are absent in cellular RNAs. We have recently reported cloning of PACT, a novel protein activator of PKR. PACT heterodimerizes with PKR and activates it by direct protein-protein interaction. Overexpression of PACT in mammalian cells leads to phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2 alpha), the cellular substrate for PKR, and leads to inhibition of protein synthesis. Here, we present evidence that endogenous PACT acts as a protein activator of PKR in response to diverse stress signals such as serum starvation, and peroxide or arsenite treatment. Following exposure of cells to these stress agents, PACT is phosphorylated and associates with PKR with increased affinity. PACT-mediated activation of PKR leads to enhanced eIF2 alpha phosphorylation followed by apoptosis. Based on the results presented here, we propose that PACT is a novel stress-modulated physiological activator of PKR.