Bruce suppresses autophagy-regulated caspase activity and wing tissue growth in Drosophila

Caspases are cysteine-aspartic proteases that mediate both lethal and non-lethal cellular outcomes, including the promotion of tissue growth. However, the mechanisms underlying the differential regulation of these activities remain unclear. We have previously shown that among the two Drosophila executioner caspases, Dcp-1 and Drice, Dcp-1 promotes tissue growth in a non-lethal manner, independent of canonical apoptotic signaling. Herein, we demonstrated that overexpressed Dcp-1, but not Drice, was activated without canonical apoptosome components. TurboID-based proximity labeling revealed distinct proximal proteomes, among which Sirtuin 1, an Atg8a deacetylase, which promotes autophagy, was specifically required for Dcp-1 activation. Autophagy-related genes, including Bcl-2 family members Debcl and Buffy, are required for Dcp-1 activation. Structure-based prediction using AlphaFold3 further identified Bruce, an autophagy-regulated inhibitor of apoptosis, as a Dcp-1-specific regulator acting outside the apoptosome-mediated pathway. Physiologically, Bruce suppresses wing tissue growth. These findings indicate that non-lethal Dcp-1 activity is governed by the autophagy-Bruce axis, enabling distinct non-lethal functions independent of cell death.