Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria
Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria
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DOI：
10.1074/jbc.m108029200
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发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Alnemri, ES
中科院分区：
文献类型：
--
作者：
Guo, Y;Srinivasula, SM;Alnemri, ES
Caspase-2是最早发现的caspase之一，但其诱导细胞凋亡的机制尚不清楚。我们在这里表明，caspase-2从事的细胞色素c（Cyt c）和其他线粒体促凋亡因子的释放到细胞质中的细胞色素a依赖性approximatotie途径。为了支持这些观察结果，我们发现Bcl-2和Bcl-xL可以阻断半胱天冬酶-2和CRADD（具有死亡结构域的半胱天冬酶和RIP适配器）诱导的细胞死亡。与可以直接加工所有已知的半胱天冬酶酶原的半胱天冬酶-8不同，半胱天冬酶-2对其他半胱天冬酶酶原完全无活性。然而，像半胱天冬酶-8一样，生理水平的纯化的半胱天冬酶-2可以切割胞质Bid蛋白，这反过来可以触发从分离的线粒体释放Cyt c。有趣的是，caspase-2也可以直接诱导细胞色素c，AIF（凋亡诱导因子），和Smac（第二个caspase衍生的激活蛋白）从分离的线粒体的释放不依赖于Bid或其他胞质因子。caspase-2释放的Cyt c在体外足以激活Apaf-caspase-9溶酶体。总之，我们的数据表明，caspase-2是线粒体凋亡途径的直接效应子。
Caspase-2 is one of the earliest identified caspases, but the mechanism of caspase-2-induced apoptosis remains unknown. We show here that caspase-2 engages the mitochondria-dependent apoptotie pathway by inducing the release of cytochrome c (Cyt c) and other mitochondrial apoptogenic factors into the cell cytoplasm. In support of these observations we found that Bcl-2 and Bcl-xL can block caspase-2- and CRADD (caspase and RIP adaptor with death domain)-induced cell death. Unlike caspase-8, which can process all known caspase zymogens directly, caspase-2 is completely inactive toward other caspase zymogens. However, like caspase-8, physiological levels of purified caspase-2 can cleave cytosolic Bid protein, which in turn can trigger the release of Cyt c from isolated mitochondria. Interestingly, caspase-2 can also induce directly the release of Cyt c, AIF (apoptosis-inducing factor), and Smac (second mitochondria-derived activator of caspases protein) from isolated mitochondria independent of Bid or other cytosolic factors. The caspase-2-released Cyt c is sufficient to activate the Apaf-caspase-9 apoptosome in vitro. In combination, our data suggest that caspase-2 is a direct effector of the mitochondrial apoptotic pathway.