Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila.

Jung-Kun Wen,Guang-Chao Chen,Cheng-Wen Hsieh,Yi-Ting Wang,Hsiao-Man Liao,Chin-Chun Hung,Chih-Chiang Chan

doi:10.7554/elife.29338

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 Atg9 null mutant flies and found that loss of Atg9 led to shortened lifespan, locomotor defects, and increased susceptibility to stress. Atg9 loss also resulted in aberrant adult midgut morphology with dramatically enlarged enterocytes. Interestingly, inhibiting the TOR signaling pathway rescued the midgut defects of the Atg9 mutants. In addition, Atg9 interacted with PALS1-associated tight junction protein (Patj), which associates with TSC2 to regulate TOR activity. Depletion of Atg9 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.

Highlights

Autophagy is a highly regulated lysosomal degradation process by which intracellular components are degraded and recycled for cell viability and homeostasis
Our previous studies showed that Drosophila Autophagy-related gene 9 (Atg9) interacts with Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2) to regulate Jun N-terminal kinase (JNK) activation, autophagy induction, and midgut homeostasis under oxidative stress conditions (Tang et al, 2013)
The Gal4 knock-in can be used for gene expression under Atg9 endogenous regulatory elements in the Atg9 mutant background

Summary

Introduction

Autophagy is a highly regulated lysosomal degradation process by which intracellular components are degraded and recycled for cell viability and homeostasis. The autophagic pathway is controlled by a series of evolutionarily conserved autophagyrelated (Atg) proteins to generate double-membraned vesicles, the autophagosomes, which subsequently fuse with lysosomes for the degradation of their contents (Feng et al, 2014). The Atg9-containing vesicles are recruited to PAS by the Atg1-kinase complex during autophagosome formation (Rao et al, 2016; Suzuki et al, 2015). The trafficking of mAtg is important for autophagy induction, and several proteins, including Ulk, ZIPK, p38IP, TRAPPC8, TBC1D5, and the AP2 complex

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