Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation.
Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation.
复制标题
DSRNA激活的蛋白激酶的诱导将线粒体展开的蛋白质反应与肠炎的发病机理联系起来。
DOI：
10.1136/gutjnl-2011-300767
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发表时间：
2012-09
期刊：
影响因子：
24.5
通讯作者：
Haller D
中科院分区：
文献类型：
--
作者：
Rath E;Berger E;Messlik A;Nunes T;Liu B;Kim SC;Hoogenraad N;Sans M;Sartor RB;Haller D
炎症性肠病(IBD)以多种细胞应激反应为特征，包括内质网(ER)未折叠蛋白反应(UPR)。UPR代表调节细胞器容量以适应细胞需求的自动调节途径。线粒体也有类似的机制，线粒体UPR(MtUPR)。肠上皮细胞(IECS)中的ER UPR有助于肠道炎症的发展，由于线粒体的改变和功能障碍与IBD的发病机制有关，作者将mtUPR描述为肠道炎症的背景。用截短型鸟氨酸转氨甲基酶选择性地诱导小鼠IEC细胞线粒体UPR。用葡聚糖硫酸钠(DSS)对双链RNA活化蛋白激酶基因敲除小鼠(PKR)体内诱导IEC应激，并检测其对DSS诱导的结肠炎的敏感性。应用免疫组织化学和Western印迹分析检测IBD患者和小鼠结肠炎模型肠上皮细胞线粒体伴侣蛋白60(CPN60)和PKR的表达水平。截短型鸟氨酸转氨酰胺酶可选择性诱导线粒体UPR，并通过募集PKR激活真核细胞翻译起始因子2α和cJun的磷酸化。利用药物抑制剂和小分子抑制核糖核酸，作者发现线粒体UPR诱导的eIF2α的磷酸化和转录因子激活(cJun/AP1)依赖于线粒体蛋白水解酶ClpP和胞浆激酶PKR的活性。PKR−/−小鼠在DSS治疗早期未能诱导IECs产生CPN60，随后对DSS诱导的结肠炎表现出几乎完全的抵抗。在炎症条件下，IBDS患者和两种结肠炎小鼠模型的原代IEC显示出强烈的mtUPR标志蛋白CPN60的诱导，与PKR的表达增强相关。PKR通过eIF2α磷酸化和AP1活化将mtUPR整合到与疾病相关的ER UPR中。在IBD小鼠模型和患者的IECS中观察到mtUPR和PKR的诱导。作者的结果表明，PKR可能将线粒体应激与肠道炎症联系起来。
Inflammatory bowel diseases (IBDs) feature multiple cellular stress responses, including endoplasmic reticulum (ER) unfolded protein responses (UPRs). UPRs represent autoregulatory pathways that adjust organelle capacity to cellular demand. A similar mechanism, mitochondrial UPR (mtUPR), has been described for mitochondria. ER UPR in intestinal epithelial cells (IECs) contributes to the development of intestinal inflammation, and since mitochondrial alterations and dysfunction are implicated in the pathogenesis of IBDs, the authors characterised mtUPR in the context of intestinal inflammation. Truncated ornithine transcarbamylase was used to selectively induce mtUPR in a murine IEC line. Dextran sodium sulphate (DSS) was administered to PKR (double-stranded-RNA-activated protein kinase) knockout mice to induce IEC stress in vivo and to test for their susceptibility to DSS-induced colitis. Expression levels of the mitochondrial chaperone chaperonin 60 (CPN60) and PKR were quantified in IECs from patients with IBDs and from murine models of colitis using immunohistochemistry and Western blot analysis. Selective mtUPR induction by truncated ornithine transcarbamylase transfection triggered the phosphorylation of eukaryotic translation initiation factor (eIF) 2α and cJun through the recruitment of PKR. Using pharmacological inhibitors and small inhibitory RNA, the authors identified mtUPR-induced eIF2α phosphorylation and transcription factor activation (cJun/AP1) as being dependent on the activities of the mitochondrial protease ClpP and the cytoplasmic kinase PKR. Pkr−/− mice failed to induce CPN60 in IECs upon DSS treatment at early time points and subsequently showed an almost complete resistance to DSS-induced colitis. Under inflammatory conditions, primary IECs from patients with IBDs and two murine models of colitis exhibited a strong induction of the mtUPR marker protein CPN60 associated with enhanced expression of PKR. PKR integrates mtUPR into the disease-relevant ER UPR via eIF2α phosphorylation and AP1 activation. Induction of mtUPR and PKR was observed in IECs from murine models and patients with IBDs. The authors’ results indicate that PKR might link mitochondrial stress to intestinal inflammation.