The cellular inhibitor of the PKR protein kinase, P58IPK, is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity
The cellular inhibitor of the PKR protein kinase, P58IPK, is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity
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DOI：
10.1074/jbc.274.6.3797
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发表时间：
1999-02-05
影响因子：
4.8
通讯作者：
Katze, MG
中科院分区：
文献类型：
--
作者：
Melville, MW;Tan, SL;Katze, MG
p58（IPK）是三肽重复序列和J结构域蛋白家族的一员，其抑制双链RNA激活的蛋白激酶PKR的能力首先被认识。PKR是干扰素诱导的宿主防御病毒感染的一部分，并通过α亚基上真核起始因子2的磷酸化下调翻译起始。P58（IPK）在流感病毒感染时被激活，并通过直接的蛋白质-蛋白质相互作用抑制PKR。以前，我们证明了分子伴侣热休克蛋白40（hsp 40）是p58（IPK）的负调节因子。我们现在可以报告，流感病毒激活p58（IPK）途径，通过促进hsp 40从p58（IPK）在感染过程中的解离。我们还发现，P58（IPK）-热休克40协会被破坏，这表明在没有病毒感染的情况下，P58（IPK）的调节作用。PKR途径甚至更复杂，因为我们在这份报告中表明，分子伴侣，HSP/HSC 70，是一个三聚体复合物与HSP 40和p58（IPK）的组成部分。此外，与其他J结构域蛋白一样，p58（IPK）也能刺激Hsc 70的ATP酶活性。综合以上结果，我们的数据表明，p58（IPK）可能是一种共伴侣蛋白，指导hsp/Hsc 70重折叠，从而抑制激酶功能。
p58(IPK), a member of the tetratricopeptide repeat and J-domain protein families, was first recognized for its ability to inhibit the double-stranded RNA-activated protein kinase, PKR. PKR is part of the interferon-induced host defense against viral infection, and down-regulates translation initiation via phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit. P58(IPK) is activated in response to infection by influenza virus, and inhibits PKR through direct protein-protein interaction. Previously, we demonstrated that the molecular chaperone heat shock protein 40 (hsp40) was a negative regulator of p58(IPK). We could now report that influenza virus activates the p58(IPK) pathway by promoting the dissociation of hsp40 from p58(IPK) during infection. We also found that the P58(IPK)-hsp40 association was disrupted during recovery from heat shock, which suggested a regulatory role for P58(IPK) in the absence of virus infection. The PKR pathway is even more complex as we show in this report that the molecular chaperone, hsp/Hsc70, was a component of a trimeric complex with hsp40 and p58(IPK). Moreover, like other J-domain proteins, p58(IPK) stimulated the ATPase activity of Hsc70, Taken together, our data suggest that p58(IPK) is a co-chaperone, possibly directing hsp/Hsc70 to refold, and thus inhibit kinase function.