The Protease Omi Cleaves the Mitogen-Activated Protein Kinase Kinase MEK1 to Inhibit Microglial Activation
The Protease Omi Cleaves the Mitogen-Activated Protein Kinase Kinase MEK1 to Inhibit Microglial Activation
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蛋白酶 Omi 裂解丝裂原激活的蛋白激酶 MEK1 以抑制小胶质细胞激活
DOI：
10.1126/scisignal.2002946
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发表时间：
2012-08-21
影响因子：
7.3
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
--
作者：
Hu, Qingsong;Li, Bin;Wang, Guanghui
帕金森病的炎症反应与疾病的发病机制密切相关。Omi基因的突变编码蛋白酶Omi，与人类和小鼠模型中的神经变性和帕金森病有关。在mnd2（运动神经元变性2）小鼠中发生的严重神经变性和神经炎症是由Omi的蛋白酶活性通过点突变S276C丧失引起的;然而，诱导神经变性的Omi的底物是未知的。我们发现Omi是小胶质细胞产生炎症分子所必需的，小胶质细胞是中枢神经系统中的常驻巨噬细胞。Omi通过切割上游激酶MEK1（丝裂原活化或细胞外信号调节蛋白激酶激酶1）抑制丝裂原活化蛋白激酶（MAPK）细胞外信号调节激酶1和2（ERK 1/2）的活化。小胶质细胞系中Omi的敲低导致ERK 1/2的活化，并导致I kappa B α [核因子B（NF-κ B B）的α抑制剂]的降解，导致NF-κ B活化和编码炎性分子（如肿瘤坏死因子-α和诱导型一氧化氮合酶）的基因表达。由Omi敲低诱导的炎症分子的产生被MEK1特异性抑制剂U0126阻断。此外，在小胶质细胞系中表达蛋白酶缺陷的S276C Omi突变体对MEK 1裂解或ERK 1/2活化没有影响。在mnd2小鼠的大脑中，我们观察到编码炎症分子的几个基因的转录增加，以及星形胶质细胞和小胶质细胞的激活。因此，我们的研究表明Omi是一种抑制神经炎症的内在细胞因子。
Inflammation in Parkinson's disease is closely associated with disease pathogenesis. Mutations in Omi, which encodes the protease Omi, are linked to neurodegeneration and Parkinson's disease in humans and in mouse models. The severe neurodegeneration and neuroinflammation that occur in mnd2 (motor neuron degeneration 2) mice result from loss of the protease activity of Omi by the point mutation S276C; however, the substrates of Omi that induce neurodegeneration are unknown. We showed that Omi was required for the production of inflammatory molecules by microglia, which are the resident macrophages in the central nervous system. Omi suppressed the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 and 2 (ERK1/2) by cleaving the upstream kinase MEK1 (mitogen-activated or extracellular signal-regulated protein kinase kinase 1). Knockdown of Omi in microglial cell lines led to activation of ERK1/2 and resulted in degradation of I kappa B alpha [alpha inhibitor of nuclear factor kappa B (NF-kappa B)], resulting in NF-kappa B activation and the expression of genes encoding inflammatory molecules, such as tumor necrosis factor-alpha and inducible nitric oxide synthase. The production of inflammatory molecules induced by the knockdown of Omi was blocked by the MEK1-specific inhibitor U0126. Furthermore, expression of the protease-deficient S276C Omi mutant in a microglial cell line had no effect on MEK1 cleavage or ERK1/2 activation. In the brains of mnd2 mice, we observed increased transcription of several genes encoding inflammatory molecules, as well as activation of astrocytes and microglia. Therefore, our study demonstrates that Omi is an intrinsic cellular factor that inhibits neuroinflammation.