Regulation of the Atg1 complex by TOR and PKA signaling in Drosophila autophagy

Autophagy provides eukaryotic cells with a means of degrading defective macromolecules and organelles, and has recently been implicated in a wide range of human diseases including neurodegenerative diseases and cancer. A large number of genes with conserved roles of autophagy have been identified in several multicellular organisms; however, concepts about the regulation of autophagy are still based largely on models from yeast, in which target of rapamycin (TOR) acts upstream to inhibit autophagy by down-regulating the assembly and activity of an Atg1/Atg13/Atg17 kinase complex. Although orthologs of the Atg1 kinase have been shown to be critical for autophagy induction in Drosophila and mammalian cells, the regulatory mechanisms have remained unclear.;This study first demonstrated that the Drosophila ortholog of Atg13 is required for autophagy in response to starvation and developmental cues. Unlike its yeast counterpart, fly Atg13 constitutively forms a complex with Atg1 and this interaction with Atg13 enhances Atg1 activity, supporting a positive role of Atg13 in autophagy. However, the simultaneous increases in Atg1 kinase activity to auto-phosphorylate the Atg1/Atg13 complex and in the accessibility of Atg1-Atg13 complex toward inhibitory TOR signaling suggest that Drosophila Atg13 possesses unique dual roles (pro- and antiautophagy) which are distinct from the yeast model. Moreover, Atg1 and Atg13 function together to repress TOR signaling, partly by recruiting TOR to the Atg1/Atg13 complex away from its active loci, reflecting a strong inhibitory feedback loop between these proteins.;In addition to the regulation by TOR signaling, yeast Atg1 and Atg13 have also been shown to serve as direct substrates for protein kinase A (PKA), which acts to inhibit autophagy in S. cerevisiae. In contrast to this inhibitory function in yeast, PKA is essential for autophagy in Drosophila and the catalytic activity of PKA is critical for autophagy induction. Other than modulating the activity of Atg1/Atg13 complex, PKA also down-regulates TOR signaling activity. The interaction of PKA and TSC suggests that PKA may play a novel role to regulate TOR through TSC/Rheb and PKA may act as a key signal to direct the induction of autophagy by relieving the TOR-dependent inhibition of Atg1/Atg13.;Collectively, this study has uncovered several significant findings in regard to the regulation of autophagy in higher eukaryotic cells using Drosophila as a model and also presents an excellent example to demonstrate that yeast and higher eukaryotic organisms share similar autophagic protein sets, but utilize these factors through different mechanisms to regulate autophagy. Together, a detailed understanding of these mechanisms will be beneficial to autophagy-based therapies for human disease.