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Autophagy Takes Flight in Drosophila

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Autophagy Takes Flight in Drosophila FEBS Letters 584 (2010) 1342–1349 journal homepage: www.FEBSLetters.org Review Autophagy takes flight in Drosophila Yu-Yun Chang, Thomas P. Neufeld * University of Minnesota, Department of Genetics, Cell Biology, and Development, 6-160 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA article info abstract Article history: Drosophila has been shown to be a powerful model to study autophagy, whose regulation involves a Received 5 December 2009 core machinery consisting of Atg proteins and upstream signaling regulators similar to those in Revised 6 January 2010 yeast and mammals. The conserved role in degrading proteins and organelles gives autophagy an Accepted 7 January 2010 important function in coordinating several cellular processes as well as in a number of pathological Available online 13 January 2010 conditions. This review summarizes key studies in Drosophila autophagy research and discusses Edited by Noboru Mizushima potential questions that may lead to better understanding of the roles and regulation of autophagy in higher eukaryotes. 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: Ó Autophagy-related gene 1 Unc-51 like kinase 1 Vps34 Jun-N-terminal kinase Target of rapamycin 1. Introduction mechanism involving a series of Atg proteins, first identified by systematic screens in yeast [2]. The core proteins for autophagy in- Autophagy is a conserved process in which cytoplasmic pro- clude three major groups, whose functions correspond to the steps teins or organelles are non-selectively packaged into lysosomes of autophagosome formation [1]. The induction signal is trans- (or vacuoles in yeast) for degradation. Autophagic substrates are duced through an autophagy-related gene 1 (Atg1) kinase com- broken down to small molecules that are recycled for macromolec- plex; this directs the membrane nucleation of autophagosomes ular synthesis or used for generating energy, and therefore autoph- through a second protein complex containing the PI(3)-kinase agy is considered as an adaptive system that allows cells to survive Vps34; finally, vesicle expansion is mediated by two ubiquitin-like starvation. In addition to this non-selective form of autophagy, groups, Atg8 and Atg5–Atg12–Atg16. The matured autophago- studies from the last decade have identified subsets of selective somes then fuse with lysosomes with the help of a set of general autophagic processes that specifically degrade intracellular organ- docking proteins to degrade components inside autolysosomes. To- elles, such as mitochondria (mitophagy), endoplasmic reticulum gether with the target of rapamycin (TOR), a conserved regulatory (reticulophagy) or peroxisomes (pexophagy) [1]. These specific kinase that inhibits autophagy, these molecules form a complex forms of autophagy provide an alternative way to clear damaged network for the regulation of autophagy [1]. organelles, which can be toxic if accumulated to high levels. In The short life cycle and powerful genetics of Drosophila, along mammals, autophagy has been implicated in several pathological with a physiology comparable to mammals, has made this organ- conditions, such as neurodegenerative diseases, tumors and patho- ism a handy model system for a wide variety of experimental ques- genic infections. Collectively, autophagy is an important cellular tions. Together with yeast and mammalian cultured cells where process with multiple functions across species. autophagy is extensively studied, Drosophila has provided a useful The delivery of autophagic substrates occurs through special- model to dissect the molecular mechanisms and the physiological ized double-membraned vesicles called autophagosomes. The for- roles of autophagy in vivo. Autophagy is inducible by starvation in mation of autophagosomes requires a tightly controlled the Drosophila larval fat body, an analogous organ to mammalian liver, and studies of this response have contributed to our under- standing of nutrient-dependent regulation of autophagy. In addi- Abbreviations: Atg1, autophagy-related gene 1; TOR, target of rapamycin; PI3K, tion, high levels of autophagy are observed in certain dying cells phosphoinositide 3-kinase; Ulk1, Unc-51 like kinase 1; S6K, RPS6-p70-protein during metamorphosis and oogenesis in Drosophila, and appear kinase; JNK, Jun-N-terminal kinase to act in concert with the apoptotic machinery in these contexts * Corresponding author. Fax: +1 612 625 5158. E-mail addresses: [email protected] (Y.-Y. Chang), [email protected] (T.P. to promote cell elimination. The roles of autophagy in aging, Neufeld). neurodegeneration and oxidative stress have also been effectively 0014-5793/$36.00 Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2010.01.006 Y.-Y. Chang, T.P. Neufeld / FEBS Letters 584 (2010) 1342–1349 1343 addressed in this system. Through these studies, several Drosophila and metazoans. The well-established yeast model has shown that genes have been identified for their roles in regulating autophagy, phosphorylation of Atg13 by TOR signaling disrupts the interaction including a group of upstream signaling molecules and the essen- of Atg1 and Atg13. Upon starvation, Atg13 is dephosphorylated and tial Atg homologs (Table 1). These genes all share evolutionary con- quickly binds Atg1 to turn on autophagy [5]. In contrast to this servation across species and together they depict the molecular yeast model, in which the interaction of Atg1 and Atg13 is limited mechanism of autophagy, forming the basis for the applications to starved cells, Drosophila Atg1 and Atg13 interact constitutively of autophagy in human diseases in the Drosophila model. There- regardless of nutrition conditions [6]. Similarly, the mammalian fore, studies in Drosophila can contribute considerably to our Atg1 homolog Unc-51 like kinase 1 (Ulk1) forms a 3MDa complex understanding of the autophagic process. Here, we summarize re- with Atg13, Atg101 and FIP200 that is stable under both fed and cent advances in our knowledge of autophagy function and regula- starved conditions [7,8]. These observations indicate a regulatory tion from experiments in the Drosophila system. discrepancy in yeast and higher eukaryotes, in which the basal autophagy is constantly maintained (Fig. 2). 2. Autophagy regulation: TOR and the Atg1 kinase complex Whereas the yeast Atg1 complex contains at least eight proteins and mammalian Ulk1 can form a 3MDa complex, the number of With its multiple functions, autophagy is a tightly regulated Drosophila Atg1-interacting proteins for autophagy regulation re- process under the control of several intracellular signaling net- mains to be determined. Among 18 Drosophila proteins that have works. The highly conserved TOR pathway is an important compo- been identified as potential Atg1-interactors by yeast two-hybrid nent of these networks, integrating multiple cellular responses to (http://www.thebiogrid.org/), thus far only Atg13 has been shown growth factors, nutrients and energy levels (Fig. 1A). Recent work to play a role in autophagy [6]. Drosophila Atg1 has also been in a number of systems have identified the Ser/Thr protein kinase shown to form a complex with the kinesin heavy chain adaptor Atg1 as a central target of TOR in directing the formation of auto- protein Unc-76, which has an important function in axonal trans- phagosomes [1]. Loss of Atg1 blocks the formation of autophago- port that is distinct from the role of Atg1 in autophagy [9]. Collec- somes, and consensus observations across species have placed tively, Drosophila Atg1 may exert distinct functions by recruiting Atg1 downstream of TOR [3–5]. The ability of Atg1 to regulate different partners, and in order to fully understand the role of autophagy relies on a group of interacting proteins without enzy- Atg1 in autophagy control, discovering Atg1-interacting proteins matic activities. In yeast, Atg13 and Atg17 are two major compo- specific to autophagy regulation will be a critical task. nents of a multi-protein Atg1 complex [5]. Atg1 activity is Given that Atg1 is a protein kinase, how the kinase activity of depleted in atg13 or atg17 mutant cells and autophagosome forma- Atg1 is involved in autophagy is important to address. Atg1 kinase tion is greatly impaired in these lines. Whereas clear homologs of activity increases after starvation both in yeast and mammalian Atg17 have not been identified in Drosophila and other higher cells, suggesting this activity is regulated by nutrition cues and eukaryotes, Atg13 is indispensable for autophagy in both yeast contributes to autophagosome formation [5,10]. In addition, Atg1 Table 1 The core genes for autophagy in Drosophila. Name Functions Confirmed Role in Autophagy References Insulin-TOR signaling pathway InR Insulin-like receptor Yes (inhibition) [3,38,45] PI3K PI3K class I Yes (inhibition) [3,27–28] Rheb Ras small GTPase family Yes (inhibition) [3] TSC1/TSC2 GTPase-activating protein (GAP) Yes [3] TOR PIK-family Ser/Thr protein kinase Yes (inhibition) [3] Autophagosome induction Atg1 Ser/Thr protein kinase Yes [3,6,12,27] Atg13 Atg1 complex Yes [6] FIP200 (CG1347) Atg1 complex ? Atg101 (CG7053) Atg1 complex ? Autophagosome nucleation Atg6 Vps34 complex Yes [3,27] Ser/Thr protein kinase Vps15 Vps34 complex Yes [16] PI3K class III Vps34 Vps34 complex Yes [16] Atg14 (CG11877) Vps34 complex ? UVRAG (CG6116) Vps34 complex ? Rubicon (CG12772) Vps34 complex ? Autophagosome expansion Atg3 E2-like
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