Ubiquitination of secretory granules promotes their crinophagic degradation in Drosophila

Gland cells dynamically regulate their secretory granule content via balancing synthesis, maturation, secretion, and lysosomal degradation (crinophagy). However, the signal(s) leading to crinophagic breakdown of secretory granules are unknown. Here, we show that ubiquitination of unreleased or low-grade glue-containing secretory granules marks these vesicles for crinophagy in larval salivary gland cells of Drosophila. We identify the ubiquitin ligase Cnot4 as a key mediator of glue granule ubiquitination. Loss of Cnot4 prevents ubiquitination and impairs granule fusion with lysosomes. Overexpression of Cnot4 induces premature crinophagy via ectopic ubiquitination of granules. Our work establishes that Cnot4-dependent ubiquitination of secretory granules is a key trigger of crinophagy in Drosophila, paving the way for further analysis of this barely characterized degradation route in metazoans.