Department of Neurology, The Second People's Hospital of Dongying, Shandong Province, 257335, China.
Department of Neurology, People's Hospital of Dongying City, Dongying, Shandong Province, 257091, China.
Biochem Biophys Res Commun. 2019 Sep 3;516(4):1272-1278. doi: 10.1016/j.bbrc.2019.06.042. Epub 2019 Jul 10.
Cerebral ischemia is a leading cause of death and long-term disability in the world. Multiple signaling pathways play essential roles in the process. Therefore, identifying the unknown important modulators of these pathways may supply promising therapeutic targets for the treatment of cerebral ischemia. Ubiquitin-specific protease 10 (USP10) is a member of the ubiquitin-specific protease family of cysteine proteases with enzymatic activity to cleave ubiquitin from ubiquitin-conjugated protein substrates, and is involved in multiple pathologies. However, the effects of USP10 in cerebral ischemia-reperfusion (I/R) injury remain unclear. Here, we reported that USP10 expression was markedly decreased in wild type (WT) mice after cerebral I/R injury. USP10 knockout (KO) mice showed significantly elevated infarct size and the neurological deficit score after cerebral I/R operation. USP10 deletion also promoted inflammatory response in ischemic penumbra of cortical regions by further accelerating nuclear factor κB (NF-κB) signaling pathway. In addition, apoptosis was markedly induced in USP10-knockout mice after cerebral I/R injury compared to the WT mice. The c-Jun N-terminal kinase-mitogen-activated protein kinase (JNK-MAPK) signaling induced by cerebral I/R injury was further aggravated in USP10-KO mice. Finally, USP10 was found to display protective effects against cerebral I/R injury through direct interaction with transforming growth factor β-activated kinase 1 (TAK1). Thus, USP10 might be a protective factor in cerebral I/R injury. Modulation of USP10/TAK1 might be a promising strategy to prevent this pathological process.
脑缺血是世界范围内死亡和长期残疾的主要原因。多种信号通路在这一过程中起着至关重要的作用。因此，确定这些通路中未知的重要调节剂可能为脑缺血的治疗提供有希望的治疗靶点。泛素特异性蛋白酶 10（USP10）是一种具有酶活性的泛素特异性蛋白酶家族的半胱氨酸蛋白酶，能够从泛素化蛋白底物上切割泛素，参与多种病理过程。然而，USP10 在脑缺血再灌注（I/R）损伤中的作用尚不清楚。在这里，我们报道了野生型（WT）小鼠脑 I/R 损伤后 USP10 表达明显下调。USP10 敲除（KO）小鼠在脑 I/R 手术后梗死面积和神经功能缺损评分明显升高。USP10 缺失还通过进一步加速核因子 κB（NF-κB）信号通路，促进皮质区域缺血半影区的炎症反应。此外，与 WT 小鼠相比，USP10 敲除小鼠脑 I/R 损伤后凋亡明显增加。脑 I/R 损伤诱导的 c-Jun N 末端激酶-丝裂原活化蛋白激酶（JNK-MAPK）信号在 USP10-KO 小鼠中进一步加重。最后，发现 USP10 通过与转化生长因子β激活激酶 1（TAK1）的直接相互作用对脑 I/R 损伤具有保护作用。因此，USP10 可能是脑 I/R 损伤的保护因子。USP10/TAK1 的调节可能是预防这一病理过程的一种有前途的策略。
