Ubiquitination of secretory granules promotes crinophagic degradation in Drosophila

Gland cells dynamically regulate their secretory granule content via balancing the rates of synthesis, maturation, secretion, and lysosomal degradation (crinophagy). The signal(s) leading to crinophagic breakdown of secretory granules are unknown. Here we show that dynamic 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 and the deubiquitinating enzyme Usp7 as mediators of glue granule ubiquitination and deubiquitination, respectively. Loss of either Cnot4 or Usp7 impairs glue granule fusion with lysosomes. Overexpression of Cnot4 induces premature crinophagy while Usp7 overexpression prevents developmental crinophagy via modulation of glue granule ubiquitination status. Our work establishes that 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.