Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Cell Rep. 2013 Dec 26;5(6):1481-8. doi: 10.1016/j.celrep.2013.11.030. Epub 2013 Dec 19.
The mitochondrial outer membrane is a major site of apoptosis regulation across phyla. Human and C. elegans Bcl-2 family proteins and Drosophila Hid require the C-terminal tail-anchored (TA) sequence in order to insert into the mitochondrial membrane, but it remains unclear whether cytosolic proteins actively regulate the mitochondrial localization of these proteins. Here, we report that the cdk7 complex regulates the mitochondrial localization of Hid and its ability to induce apoptosis. We identified cdk7 through an in vivo RNAi screen of genes required for cell death. Although CDK7 is best known for its role in transcription and cell-cycle progression, a hypomorphic cdk7 mutant suppressed apoptosis without impairing these other known functions. In this cdk7 mutant background, Hid failed to localize to the mitochondria and failed to bind to recombinant inhibitors of apoptosis (IAPs). These findings indicate that apoptosis is promoted by a newly identified function of CDK7, which couples the mitochondrial localization and IAP binding of Hid.
线粒体的外膜是跨门调节细胞凋亡的主要场所。人类和秀丽隐杆线虫 Bcl-2 家族蛋白和果蝇 Hid 需要 C 末端尾部锚定（TA）序列才能插入线粒体膜，但目前尚不清楚细胞质蛋白是否主动调节这些蛋白在线粒体中的定位。在这里，我们报告说，cdk7 复合物调节 Hid 的线粒体定位及其诱导细胞凋亡的能力。我们通过细胞死亡所需基因的体内 RNAi 筛选鉴定出 cdk7。虽然 CDK7 最出名的是它在转录和细胞周期进展中的作用，但 cdk7 的一个功能不全突变体在不损害这些其他已知功能的情况下抑制细胞凋亡。在这个 cdk7 突变体背景下，Hid 未能定位到线粒体，也未能与重组凋亡抑制剂（IAPs）结合。这些发现表明，细胞凋亡是由 CDK7 的一个新发现的功能促进的，该功能将 Hid 的线粒体定位和 IAP 结合耦联起来。
