Insulin-degrading Enzyme (IDE) A NOVEL HEAT SHOCK-LIKE PROTEIN
Insulin-degrading Enzyme (IDE) A NOVEL HEAT SHOCK-LIKE PROTEIN
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DOI：
10.1074/jbc.m112.393108
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发表时间：
2013-01-25
影响因子：
4.8
通讯作者：
Marini, Stefano
中科院分区：
文献类型：
--
作者：
Tundo, Grazia Raffaella;Sbardella, Diego;Marini, Stefano
胰岛素降解酶（IDE）是一种高度保守的锌金属肽酶，广泛分布于人体组织中，尤其在大脑、肝脏和肌肉中含量丰富。历史上，IDE 活性与胰岛素和 β-淀粉样蛋白分解代谢有关。然而，在过去的十年中，一些实验结果表明，IDE 还参与多种病理生理过程，包括泛素清除和水痘带状疱疹病毒感染。在这项研究中，我们证明，暴露于不同应激的正常细胞和恶性细胞会以类似热休克蛋白（HSP）的方式显着上调 IDE。此外，我们将注意力集中在肿瘤细胞上，并报告称：(i) IDE 在中枢神经系统 (CNS) 肿瘤体内过度表达； (ii) IDE 沉默抑制神经母细胞瘤 (SHSY5Y) 细胞增殖并引发细胞死亡； (iii) IDE 抑制伴随着 SHSY5Y 细胞中多聚泛素化蛋白含量的减少以及与蛋白酶体和泛素的共免疫沉淀。在这项工作中，我们提出了 IDE 作为热休克蛋白的新作用，对细胞生长调节和癌症进展具有影响，从而提出了 IDE 作为抗癌靶点的有趣假设。
Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase that is ubiquitously distributed in human tissues, and particularly abundant in the brain, liver, and muscles. IDE activity has been historically associated with insulin and beta-amyloid catabolism. However, over the last decade, several experimental findings have established that IDE is also involved in a wide variety of physiopathological processes, including ubiquitin clearance and Varicella Zoster Virus infection. In this study, we demonstrate that normal and malignant cells exposed to different stresses markedly up-regulate IDE in a heat shock protein (HSP)-like fashion. Additionally, we focused our attention on tumor cells and report that (i) IDE is overexpressed in vivo in tumors of the central nervous system (CNS); (ii) IDE-silencing inhibits neuroblastoma (SHSY5Y) cell proliferation and triggers cell death; (iii) IDE inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells. In this work, we propose a novel role for IDE as a heat shock protein with implications in cell growth regulation and cancer progression, thus opening up an intriguing hypothesis of IDE as an anticancer target.