Ubiquitination of secretory granules promotes their crinophagic degradation in Drosophila

Background: Gland cells dynamically regulate their secretory granule content via balancing the rates of synthesis, maturation, secretion, and lysosomal degradation (crinophagy). However, the signal(s) leading to crinophagic breakdown of secretory granules are unknown. Results: 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 . Furthermore, we identify the ubiquitin ligase Cnot4 as a key mediator of glue granule ubiquitination. Strikingly, loss of Cnot4 prevents ubiquitination and impairs glue granule fusion with lysosomes, while overexpression of Cnot4 induces premature crinophagy via ectopic ubiquitination of glue granules. Conclusions: 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.