Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in <i>Drosophila</i>.

Abstract

Autophagy is essential for maintaining cellular homeostasis and survival under various stress conditions. Autophagy-related gene 9 (Atg9) encodes a multipass transmembrane protein thought to act as a membrane carrier for forming autophagosomes. However, the molecular regulation and physiological importance of Atg9 in animal development remain largely unclear. Here, we generated <i>Atg9</i> null mutant flies and found that loss of <i>Atg9</i> led to shortened lifespan, locomotor defects, and increased susceptibility to stress. <i>Atg9</i> loss also resulted in aberrant adult midgut morphology with dramatically enlarged enterocytes. Interestingly, inhibiting the TOR signaling pathway rescued the midgut defects of the <i>Atg9</i> mutants. In addition, Atg9 interacted with PALS1-associated tight junction protein (Patj), which associates with TSC2 to regulate TOR activity. Depletion of <i>Atg9</i> caused a marked decrease in TSC2 levels. Our findings revealed an antagonistic relationship between Atg9 and TOR signaling in the regulation of cell growth and tissue homeostasis.