Calpain cleaves methionine aminopeptidase-2 in a rat model of ischemia/reperfusion.
Calpain cleaves methionine aminopeptidase-2 in a rat model of ischemia/reperfusion.
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DOI：
10.1016/j.brainres.2012.12.039
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发表时间：
2013-03-07
期刊：
影响因子：
2.9
通讯作者：
Guttmann RP
中科院分区：
文献类型：
--
作者：
Clinkinbeard T;Ghoshal S;Craddock S;Creed Pettigrew L;Guttmann RP
缺血性中风导致细胞内多种损伤信号，包括钙稳态失调。因此，钙蛋白酶的酶活性增加，钙依赖性蛋白酶被认为有助于神经元损伤。此外，由于缺血/再灌注引起的细胞应激也通过激活未折叠蛋白反应（UPR）引发蛋白质翻译的减少。在本研究中，我们发现蛋氨酸氨基肽酶2 （MetAP2）是翻译起始复合物的关键成分，是钙蛋白酶的底物。体外calpain实验表明，虽然MetAP2具有自身蛋白水解活性，但calpain也可以通过重组MetAP2产生50 kDa的稳定蛋白水解片段。这50 kDa片段，除了57 kDa片段存在于大鼠脑匀浆的体外消化中。内源性特异性钙蛋白酶抑制剂钙pastatin抑制了这些片段的产生。在体内大脑中动脉闭塞（MCAO）模型中，只观察到MetAP2的57kDa片段。这些数据表明，脑卒中中钙蛋白酶的激活可能调节metap2介导的蛋白翻译，这使得钙蛋白酶在细胞应激反应中的作用比之前确定的更大。
Ischemic stroke results in multiple injurious signals within a cell including dysregulation of calcium homeostasis. Consequently, there is an increase in the enzymatic activity of the calpains, calcium dependent proteases that are thought to contribute to neuronal injury. In addition, cellular stress due to ischemia/reperfusion also triggers a decrease in protein translation through activation of the unfolded protein response (UPR). In the present study we found that methionine aminopeptidase 2 (MetAP2), a critical component of the translation initiation complex, is a calpain substrate. In vitro calpain assays demonstrated that while MetAP2 has autoproteolytic activity, calpain also produces a stable proteolytic fragment at 50 kDa using recombinant MetAP2. This 50 kDa fragment, in addition to a 57 kDa fragment was present in in vitro digestions of rat brain homogenates. Production of these fragments was inhibited by calpastatin, the endogenous and specific inhibitor of calpain. Using an in vivo middle cerebral artery occlusion (MCAO) model only the 57kDa fragment of MetAP2 was observed.These data suggest that calpain activation in stroke may regulate MetAP2-mediated protein translation giving calpains a larger role in the cellular stress response than previously determined.
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