Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center Marburg, Marburg Center for Mind, Brain and Behavior - MCMBB, University of Marburg, Marburg, Germany.
Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany.
Cell Death Differ. 2018 Aug;25(8):1394-1407. doi: 10.1038/s41418-017-0046-7. Epub 2018 Jan 19.
The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.
抑癌基因圆柱瘤病（CYLD）是一种去泛素化酶，也是细胞增殖和炎症的关键调节因子。全基因组 siRNA 筛选将 CYLD 与受体相互作用蛋白 1（RIP1）激酶介导的细胞坏死联系起来；然而，CYLD 介导的细胞死亡的确切机制仍不清楚。因此，我们研究了 CYLD 在体外神经元细胞死亡模型中的精确作用，并评估了 CYLD 缺失是否会影响体内脑损伤。在体外，下调 CYLD 会增加 RIP1 的泛素化，阻止 RIP1/RIP3 复合物的形成，并保护神经元细胞免受氧化死亡。通过 RIP1 或 RIP3 的 siRNA 沉默或使用 necrostatin-1 抑制 RIP1 也可以达到类似的保护作用。在体内，与野生型同窝仔对照相比，CYLD 敲除小鼠对创伤诱导的脑损伤具有保护作用。这些发现揭示了 CYLD 在体外受损神经元中介导细胞死亡信号的机制，并提示 CYLD 在体内具有细胞死亡介导作用。
