ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1
ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1
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DOI：
10.1242/jcs.127340
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发表时间：
2013-05-01
影响因子：
4
通讯作者：
Alves Da Costa, Cristine
中科院分区：
文献类型：
--
作者：
Duplan, Eric;Giaime, Emilie;Alves Da Costa, Cristine
Parkin和DJ-1是两种与常染色体隐性早发性帕金森病（PD）相关的多功能蛋白，它们已被证明通过尚不清楚的机制在功能上相互作用。我们已经描述了parkin控制DJ-1的机制。Parkin通过涉及p53和内质网（ER）应激诱导的活性x- box结合蛋白- 1s （XBP-1S）的信号级联调节DJ-1的转录和蛋白水平。Parkin触发p53的转录抑制，而p53下调DJ-1蛋白和mRNA的表达。我们发现帕金森介导的DJ-1的控制完全依赖于p53。此外，我们确定p53降低XBP-1S的蛋白和mRNA水平。因此，我们发现帕金最终上调了XBP-1的水平。随后，XBP-1S与DJ-1启动子物理相互作用，从而增强其启动子反式激活、mRNA水平和蛋白质表达。这一数据通过在parkin-和p53-缺失小鼠大脑中检测DJ-1得到证实。这种转录级联被致病性帕金突变所消除，并且与泛素连接酶活性无关。我们的数据建立了一个与park无关的内质网应激相关的DJ-1调节，并确定p53和XBP-1是在细胞和体内这种信号级联中作用于parkin下游的两个主要参与者。这项工作为PD病理中观察到的未折叠蛋白反应的增加提供了机制解释，即这是由于PD相关的DJ-1控制缺陷所致。
Parkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stress-induced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin- and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a park-independent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1.