The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress.
The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress.
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DOI：
10.1038/ncb2395
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发表时间：
2011-12-18
影响因子：
21.3
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中科院分区：
文献类型：
--
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对内质网（ER）蛋白质折叠能力的过度要求导致内质网应激不可修复，并导致许多细胞退行性疾病的细胞损失，包括2型糖尿病和神经退行性疾病。传达灾难性内质网损伤线粒体凋亡机制的信号仍然知之甚少。我们使用生化方法纯化内质网应激诱导的细胞质活性，该活性导致分离线粒体释放细胞色素c。我们发现纯化的促凋亡活性的主要成分是原癌基因ct10调节激酶（CRK），这是一种没有已知催化活性的衔接蛋白。Crk-/-细胞对内质网应激诱导的凋亡具有很强的抗性。此外，在内质网胁迫下，CRK被切割，产生一个n端~14kD片段，大大增强了细胞毒性。我们在这个n端CRK片段中发现了一个假定的BCL2同源-3 （BH3）结构域，该结构域使分离的线粒体对细胞色素c的释放敏感，并且在体内突变时显著降低了CRK的凋亡活性。总之，这些结果确定了CRK是一种促凋亡蛋白，它向线粒体执行机制发出不可补救的内质网应激信号。
Excessive demands on the protein folding capacity of the endoplasmic reticulum (ER) cause irremediable ER stress and contribute to cell loss in a number of cell degenerative diseases, including type 2 diabetes and neurodegeneration. The signals communicating catastrophic ER damage to the mitochondrial apoptotic machinery remain poorly understood. We used a biochemical approach to purify a cytosolic activity induced by ER stress that causes release of cytochrome c from isolated mitochondria. We discovered that the principal component of the purified pro-apoptotic activity is proto-oncogene CT10-regulated kinase (CRK), an adaptor protein with no known catalytic activity. Crk-/- cells are strongly resistant to ER stress-induced apoptosis. Moreover, CRK is cleaved in response to ER stress to generate an N-terminal ~14kD fragment with greatly enhanced cytotoxic potential. We identified a putative BCL2 homology-3 (BH3) domain within this N-terminal CRK fragment, which sensitizes isolated mitochondria to cytochrome c release and when mutated significantly reduces CRK's apoptotic activity in vivo. Together these results identify CRK as a pro-apoptotic protein that signals irremediable ER stress to the mitochondrial execution machinery.
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