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首页> 外文期刊>Nature cell biology >The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress
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The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress

机译：衔接蛋白CRK是内质网应激的促凋亡转导子

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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 neurodegeneration12. The signals communicating catastrophic ER damage to the mitochondrial apoptotic machinery remain poorly understood36. 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 the proto-oncoprotein CRK (CTlO-regulated kinase), an adaptor protein with no known catalytic activity7. Crk~(-/-) cells are strongly resistant to ER-stress-induced apoptosis. Moreover, CRK is cleaved in response to ER stress to generate an amino-terminal M_r~14K fragment with greatly enhanced cytotoxic potential. We identified a putative BH3 (BCL2 homology 3) domain within this N-terminal CRK fragment, which sensitizes isolated mitochondria to cytochrome c release and when mutated significantly reduces the apoptotic activity of CRK in vivo. Together these results identify CRK as a pro-apoptotic protein that signals irremediable ER stress to the mitochondrial execution machinery.
机译：对内质网（ER）的蛋白质折叠能力的过度需求会导致无法缓解的ER压力，并导致许多细胞退行性疾病（包括2型糖尿病和神经退行性疾病）中的细胞丢失12。传达对线粒体凋亡机制造成灾难性内质网损害的信号仍然知之甚少36。我们使用了一种生物化学方法来纯化由内质网应激诱导的细胞溶质活性，内质网应激会导致细胞色素c从分离的线粒体中释放出来。我们发现，纯化的促凋亡活性的主要成分是原癌蛋白CRK（CT10调节的激酶），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较强的抵抗力。此外，响应于ER应激，CRK被切割以产生具有大大增强的细胞毒性潜力的氨基末端M_r〜14K片段。我们在此N端CRK片段中鉴定了一个推测的BH3（BCL2同源性3）域，该域可使分离的线粒体对细胞色素c的释放敏感，并在突变时显着降低了体内CRK的凋亡活性。这些结果共同证明CRK是一种促凋亡蛋白，向线粒体执行机构发出无法补救的ER应激信号。

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