Milleron Rania S, Bratton Shawn B
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712; Center for Research on Environmental Disease, The University of Texas at Austin, Austin, Texas 78712.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712; Center for Research on Environmental Disease, The University of Texas at Austin, Austin, Texas 78712; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712.
J Biol Chem. 2006 Jun 23;281(25):16991-17000. doi: 10.1074/jbc.M512754200. Epub 2006 Apr 17.
Adaptive responses to mild heat shock are among the most widely conserved and studied in nature. More intense heat shock, however, induces apoptosis through mechanisms that remain largely unknown. Herein, we present evidence that heat shock activates an apical protease that stimulates mitochondrial outer membrane permeabilization and processing of the effector caspase-3 in a benzyloxycarbonyl-VAD-fluoromethyl ketone (polycaspase inhibitor)- and Bcl-2-inhibitable manner. Surprisingly, however, neither FADD.caspase-8 nor RAIDD.caspase-2 PIDDosome (p53-induced protein with a death domain) complexes were detected in dying cells, and neither of these initiator caspases nor the endoplasmic reticulum stress-activated caspases-4/12 were required for mitochondrial outer membrane permeabilization. Similarly, although cytochrome c was released from mitochondria following heat shock, functional Apaf-1.caspase-9 apoptosome complexes were not formed, and caspase-9 was not essential for the activation of caspase-3 or the induction of apoptosis. Thus, heat shock does not require any of the known initiator caspases or their activating complexes to promote apoptotic cell death but instead relies upon the activation of an apparently novel apical protease with caspase-like activity.
对轻度热休克的适应性反应是自然界中最为广泛保守且被深入研究的反应之一。然而，更强烈的热休克会通过很大程度上仍不明的机制诱导细胞凋亡。在此，我们提供证据表明热休克激活一种顶端蛋白酶，该蛋白酶以苄氧羰基 - VAD - 氟甲基酮（多 caspase 抑制剂）和 Bcl - 2 可抑制的方式刺激线粒体外膜通透性增加及效应 caspase - 3 的加工。然而，令人惊讶的是，在濒死细胞中未检测到 FADD.caspase - 8 或 RAIDD.caspase - 2 PIDDosome（含死亡结构域的 p53 诱导蛋白）复合物，并且线粒体外膜通透性增加既不需要这些起始 caspase 中的任何一种，也不需要内质网应激激活的 caspase - 4/12。同样，尽管热休克后细胞色素 c 从线粒体释放，但功能性的 Apaf - 1.caspase - 9 凋亡小体复合物并未形成，并且 caspase - 9 对于 caspase - 3 的激活或细胞凋亡的诱导并非必需。因此，热休克促进凋亡性细胞死亡并不需要任何已知的起始 caspase 或其激活复合物，而是依赖于一种具有 caspase 样活性的明显新型顶端蛋白酶的激活。
