Executioner caspase is proximal to Fasciclin 3 which facilitates non-lethal activation in <i>Drosophila</i> olfactory receptor neurons.

Abstract

The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins of <i>Drosophila</i> executioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated that <i>Fas3G</i> overexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically, <i>Fas3G</i> overexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.