Danial N N
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Oncogene. 2008 Dec;27 Suppl 1:S53-70. doi: 10.1038/onc.2009.44.
The BH3-only pro-apoptotic proteins are upstream sensors of cellular damage that selectively respond to specific, proximal death and survival signals. Genetic models and biochemical studies indicate that these molecules are latent killers until activated through transcriptional or post-translational mechanisms in a tissue-restricted and signal-specific manner. The large number of BH3-only proteins, their unique subcellular localization, protein-interaction network and diverse modes of activation suggest specialization of their damage-sensing function, ensuring that the core apoptotic machinery is poised to receive input from a wide range of cellular stress signals. The apoptotic response initiated by the activation of BH3-only proteins ultimately culminates in allosteric activation of pro-apoptotic BAX and BAK, the gateway proteins to the mitochondrial pathway of apoptosis. From activation of BH3-only proteins to oligomerization of BAX and BAK and mitochondrial outer membrane permeabilization, an intricate network of interactions between the pro- and anti-apoptotic members of the BCL-2 family orchestrates the decision to undergo apoptosis. Beyond regulation of apoptosis, multiple BCL-2 proteins have recently emerged as active components of select homeostatic pathways carrying other cellular functions. This review focuses on BAD, which was the first BH3-only protein linked to proximal survival signals through phosphorylation by survival kinases. In addition to findings that delineated the physiological role of BAD in apoptosis and its dynamic regulation by phosphorylation, studies pointing to new roles for this protein in other physiological pathways, such as glucose metabolism, are highlighted. By executing its 'day' and 'night' jobs in metabolism and apoptosis, respectively, BAD helps coordinate mitochondrial fuel metabolism and the apoptotic machinery.
仅含BH3结构域的促凋亡蛋白是细胞损伤的上游传感器，可选择性地响应特定的近端死亡和存活信号。遗传模型和生化研究表明，这些分子在通过转录或翻译后机制以组织限制和信号特异性方式激活之前是潜在的杀手。大量仅含BH3结构域的蛋白、其独特的亚细胞定位、蛋白质相互作用网络和多样的激活模式表明其损伤感应功能具有特异性，确保核心凋亡机制能够接收来自广泛细胞应激信号的输入。由仅含BH3结构域的蛋白激活引发的凋亡反应最终导致促凋亡蛋白BAX和BAK的变构激活，它们是凋亡线粒体途径的门户蛋白。从仅含BH3结构域的蛋白激活到BAX和BAK的寡聚化以及线粒体外膜通透性改变，BCL-2家族促凋亡和抗凋亡成员之间复杂的相互作用网络协调了细胞凋亡的决定。除了对凋亡的调节，最近多种BCL-2蛋白已成为具有其他细胞功能的特定稳态途径的活性成分。本综述重点关注BAD，它是首个通过存活激酶磷酸化与近端存活信号相关联的仅含BH3结构域的蛋白。除了阐明BAD在凋亡中的生理作用及其磷酸化动态调节的研究结果外，还突出了该蛋白在其他生理途径（如葡萄糖代谢）中的新作用。通过分别在代谢和凋亡中执行其“白天”和“夜晚”的工作，BAD有助于协调线粒体燃料代谢和凋亡机制。
