Autophagy takes flight in Drosophila

Abstract

Drosophila has been shown to be a powerful model to study autophagy, whose regulation involves a core machinery consisting of Atg proteins and upstream signaling regulators similar to those in yeast and mammals. The conserved role in degrading proteins and organelles gives autophagy an important function in coordinating several cellular processes as well as in a number of pathological conditions. This review summarizes key studies in Drosophila autophagy research and discusses potential questions that may lead to better understanding of the roles and regulation of autophagy in higher eukaryotes.

Fig 1

Three major autophagy induction routs in Drosophila. (A) Upon starvation or removal of growth factors, autophagy is induced through inhibition of TOR, which negatively regulates autophagy in well-fed organisms. The activity of TOR is under the control of Rheb and TSC1/2, both acting downstream of PI3K and AKT but with opposing effects on TOR. (B) Developmental autophagy is triggered by ecdysone signaling to eliminate tissues or organs, accompanied by the activation of cell death genes. The involvement of caspases during developmental autophagy is cell-specific. (C) JNK can direct the induction of autophagy in response to oxidative stress. Atg1 and other Atg genes are transcriptionally activated by JNK signaling, possibly through the dFOXO transcriptional factor.

Fig 2

Comparison of Atg1 complexes in yeast, Drosophila and mammals. (A) In yeast, the phosphorylation of Atg13 by TOR signaling prevents Atg13 from forming a complex with Atg1. No autophagy occurs until the phosphorylation on Atg13 is removed in response to starvation. (B) Drosophila Atg1-Atg13 complex is present constitutively in fed and starved conditions. Atg1 and Atg13 are both phosphorylated by Atg1 and TOR signaling; however, Atg1 is more sensitive to TOR signaling in fed animals while phosphorylation of Atg13 is highest under starved condition, where Atg1 activity is elevated. (C) Similar to Drosophila, mammalian Atg1 complexes show little change in composition in response to nutrient status, except that mTOR has higher affinity for the Atg1 complex under fed conditions. Although Atg1 and Atg13 are both substrates of mTOR and Atg1, similar to their Drosophila counterparts, starvation leads to decreased phosphorylation of Atg13 due to lower mTOR activity as well as higher Atg1-dependent phosphorylation of FIP200.