Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Harvard Medical School, Boston, MA 02115, USA.
Sci Adv. 2024 Oct 11;10(41):eadn0325. doi: 10.1126/sciadv.adn0325. Epub 2024 Oct 9.
In , apoptosis is inhibited by the BCL-2 homolog CED-9. Although canonically anti-apoptotic, CED-9 has a poorly understood pro-apoptotic function. CED-9 is thought to inhibit apoptosis by binding to and inhibiting the pro-apoptotic APAF-1 homolog CED-4. We show that CED-9 or CED-4 mutations located in their CED-9-CED-4 binding regions reduce apoptosis without affecting the CED-9 anti-apoptotic function. These mutant CED-9 and CED-4 proteins are defective in a CED-9-CED-4 interaction in vitro and in vivo, revealing that the known CED-9-CED-4 interaction is required for the pro-apoptotic but not for the anti-apoptotic function of CED-9. The pro-apoptotic CED-9-CED-4 interaction occurs at mitochondria. In mammals, BCL-2 family members can activate APAF-1 via cytochrome c release from mitochondria. The conserved role of mitochondria in CED-9/BCL-2-dependent CED-4/APAF-1 activation is notable and suggests that understanding how CED-9 promotes apoptosis in could inform the understanding of mammalian apoptosis and how disruptions of apoptosis promote certain human disorders.
在 中，凋亡被 BCL-2 同源物 CED-9 抑制。尽管 CED-9 通常具有抗凋亡作用，但它具有一种理解甚少的促凋亡功能。人们认为 CED-9 通过与促凋亡 APAF-1 同源物 CED-4 结合并抑制其活性来抑制凋亡。我们发现，位于其 CED-9-CED-4 结合区域的 CED-9 或 CED-4 突变会减少凋亡，而不影响 CED-9 的抗凋亡功能。这些突变的 CED-9 和 CED-4 蛋白在体外和体内均无法进行 CED-9-CED-4 相互作用，表明已知的 CED-9-CED-4 相互作用对于 CED-9 的促凋亡功能而非抗凋亡功能是必需的。促凋亡的 CED-9-CED-4 相互作用发生在线粒体。在哺乳动物中，BCL-2 家族成员可以通过线粒体释放细胞色素 c 来激活 APAF-1。线粒体在 CED-9/BCL-2 依赖性 CED-4/APAF-1 激活中的保守作用值得注意，这表明了解 CED-9 如何促进 中的凋亡可以为理解哺乳动物凋亡以及凋亡失调如何促进某些人类疾病提供信息。
