Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK
Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK
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DOI：
10.1073/pnas.252341799
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Katze, MG
中科院分区：
文献类型：
--
作者：
Yan, W;Frank, CL;Katze, MG
P58（IPK）是已知通过结合其激酶结构域来抑制干扰素（IFN）诱导的、双链RNA激活的真核起始因子2alpha（elf2alpha）蛋白激酶R（PKR）的Hsp40家族成员。我们发现，在内质网（ER）未折叠蛋白的压力激活P58（IPK）基因的转录通过ER的压力响应元件在其启动子区。P58（IPK）与PKR样ER定位的eIF2 α激酶PERK相互作用并抑制该激酶，该激酶通常在ER应激反应期间被激活，以通过减弱蛋白质合成和降低ER客户蛋白负荷来保护细胞免受ER应激。磷酸化eIF2a的水平在ER应激的P58（IPK）过表达细胞中较低，并且在P58（IPK）突变细胞中增强。在ER应激反应中，PKR样ER激酶（PERK）介导的翻译抑制是短暂的，随后是翻译恢复和增强的基因表达，增加ER处理客户蛋白的能力。P58（IPK）的缺失导致两种ER应激诱导基因BiP和Chop的表达水平增加，这与P58（IPK）缺失细胞中eIF 2a磷酸化增强一致。我们的研究表明，P58（IPK）诱导ER应激反应过程中抑制PERK活性，并在ER应激反应后期PERK活性下游标志物的表达中发挥功能性作用。
P58(IPK) is an Hsp40 family member known to inhibit the interferon (IFN)-induced, double-stranded RNA-activated, eukaryotic initiation factor 2alpha (elf2alpha) protein kinase R (PKR) by binding to its kinase domain. We find that the stress of unfolded proteins in the endoplasmic reticulum (ER) activates P58(IPK) gene transcription through an ER stress-response element in its promoter region. P58(IPK) interacts with and inhibits the PKR-like ER-localized elF2alpha kinase PERK, which is normally activated during the ER-stress response to protect cells from ER stress by attenuating protein synthesis and reducing ER client protein load. Levels of phosphorylated elF2a were lower in ER-stressed P58(IPK)-overexpressing cells and were enhanced in P58(IPK) mutant cells. In the ER-stress response, PKR-like ER kinase (PERK)-mediated translational repression is transient and is followed by translational recovery and enhanced expression of genes that increase the capacity of the ER to process client proteins. The absence of P58(IPK) resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop, consistent with the enhanced elF2a phosphorylation in the P58(IPK) deletion cells. Our studies suggest that P58(IPK) induction during the ER-stress response represses PERK activity and plays a functional role in the expression of downstream markers of PERK activity in the later phase of the ER-stress response.