Hdac3 suppresses apoptosis through deacetylating and stabilizing the antiapoptotic protein Diap1

Apoptosis is a highly conserved process that eliminates unwanted or damaged cells in both physiological and pathological conditions. Dysregulation of apoptosis leads to developmental abnormalities and various diseases, such as neurodegeneration and cancer. Drosophila inhibitor of apoptosis 1 (Diap1) plays a crucial role in cell survival by inhibiting caspases and preventing apoptosis. However, under stress conditions, the prodeath proteins Rpr, Hid, and Grim (RHG) induce apoptosis by antagonizing Diap1. Despite being a key component of the apoptotic pathway, the mechanism that controls the stability of Diap1 remains unknown. Here, we find that loss of hdac3 results in the activation of apoptosis, which is completely blocked by expressing Diap1. Although Hdac3 localizes in both the cell cytoplasm and nucleus, only the cytoplasmic Hdac3 is able to suppress apoptosis induced by hdac3 deficiency, RHG overexpression, or x-ray irradiation. This finding indicates that Hdac3 exerts an antiapoptotic role independent of its canonical epigenetic functions. Loss of hdac3 decreases Diap1 protein, which is rescued by introducing cytoplasmic Hdac3. The deacetylase activity is necessary for Hdac3 to suppress apoptosis. Mechanistically, Hdac3 interacts with Diap1 to remove the acetyl group from K315 on Diap1, thereby increasing its stability. Compared with the wild-type Diap1, the acetyl-deficient mutant Diap1-K315R exhibits stronger stability and antiapoptotic activity. Last, RHG proteins compete with Hdac3 for Diap1 interaction, directing Diap1 toward degradation and triggering apoptosis. Together, these findings not only reveal the involvement of Diap1 acetylation modification in apoptosis regulation but also clarify the role of Hdac3 in apoptosis.