Editor’s corner
Editor’s corner
Autophagy 7:8, 801-802; August 2011; © 2011 Landes Bioscience
There is more to autophagy than induction Regulating the roller coaster Daniel J. Klionsky1,* and Andriy Nemchenko2 University of Michigan; Life Sciences Institute; Ann Arbor, MI USA; 2University of Texas Southwestern Medical Center; Internal Medicine—Cardiology; Dallas, TX USA
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Key words: Atg1, autophagosome, flux, lysosome, macroautophagy, phagophore, regulation, stress, TOR, Ulk1, vacuole
Considerable attention has been paid to the topic of autophagy induction. In part, this is because of the potential for modulating this process for therapeutic purposes. Of course we know that induced autophagy can also be problematic—for example, when trying to eliminate an established tumor that might be relying on autophagy for its own cytoprotective uses. Accordingly, inhibitory mechanisms have been considered; however, the corresponding studies have tended to focus on the pathways that block autophagy under noninducing conditions, such as when nutrients are available. In contrast, relatively little is known about the mechanisms for inhibiting autophagy under inducing conditions. Yet, this type of regulation must be occurring on a routine basis. We know that dysregulation of autophagy, e.g., due to improper activation of Beclin 1 leading to excessive autophagy activity, can cause cell death.1 Accordingly, we assume that during starvation or other inducing conditions there must be a mechanism to modulate autophagy. That is, once you turn it on, you do not want to let it continue unchecked. But how is autophagy downregulated when the inducing conditions still exist?
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One possibility for downregulating macroautophagy is suggested by Tom Neufeld’s lab, which showed that p70S6 kinase is a positive regulatory factor for autophagy in the Drosophila fat body.2 Accordingly, inhibition of TOR activity ultimately results in decreased p70S6K function, which in turn downregulates autophagy. An alternate suggestion from Fred Meijer and Patrice Codogno is that p70S6K acts in part by negatively regulating the class I PtdIns 3-kinase.3 In this scenario, when TOR is inhibited the decrease in p70S6K activity results in the eventual reactivation of the class I PtdIns3K, which then stimulates TOR and downregulates autophagy. Further insight into this question is provided by a relatively recent study from Adi Kimchi’s lab. The conserved protein DAP1 is an mTOR substrate that inhibits macroautophagy. In nutrient-rich conditions, active mTORC1 inhibits DAP1 so that the latter has no effect on autophagy. The inhibition of mTORC1 during nutrient starvation results in the dephosphorylation and activation of DAP1, and the subsequent inhibition of macroautophagy, which limits the magnitude of autophagy-dependent degradation.4,5 Another mechanism of regulation is indicated in studies by Li Yu and colleagues who showed that autophagy is downregulated through mTOR reactivation in an autophagy-dependent manner that requires protein degradation in autolysosomes.6 This negative feedback mechanism provides another simple means of self-regulation whereby the nutrient levels within the cell dictate whether autophagy needs to be maintained or shut down. A study described in this issue of the journal provides further support for
this mechanism, demonstrating that autophagy can be downregulated during starvation in yeast.7 Shin and Huh found that TOR activity is recovered during prolonged starvation, and that this again depends on autophagy (see Fig. 1 in the Autophagic Flux section, p. 803). These studies suggest that autophagy may cycle on and off repeatedly during starvation as nutrient supplies are consumed and then resupplied, ensuring that autophagy is maintained at optimal, and not excessive, levels. The latter mechanism, however, cannot explain how autophagy is regulated during other types of stress, suggesting that multiple control systems are involved. In closing, we introduce a new category of papers and a new section to the journal that we are calling Resource and Autophagic Flux, respectively. Resource papers will provide information that may be useful to the autophagy community, but that may not have specific mechanistic information, such as may occur with large-scale screens. For example, in this issue, see the paper from Marja Jäättelä’s lab that describes the use of a human kinome siRNA library to identify new kinases that regulate macroautophagy. Finally, we have chosen the name Autophagic Flux for the new section because it encompasses the full spectrum of the autophagic process. The schematic summary in Figure 1 of that section highlights the paper by Shin and Huh that we mention here. Our intention is to provide schematic highlights of most of the research papers in the Autophagic Flux section, providing readers with a quick overview and summary of the key point(s) of the study. We hope you find this useful; we welcome feedback.
*Correspondence to: Daniel J. Klionsky; Email:
[email protected] Submitted: 05/25/11; Accepted: 05/25/11 DOI: 10.4161/auto.7.8.16609 www.landesbioscience.com Autophagy
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References 1. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122:927-39; PMID:16179260; doi:10.1016/j.cell.2005.07.002. 2. Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell 2004; 7:167-78; PMID:15296714; doi:10.1016/j.devcel.2004.07.009. 3. Klionsky DJ, Meijer AJ, Codogno P, Neufeld TP, Scott RC. Autophagy and p70S6 kinase. Autophagy 2005; 1:59-61; PMID:16874035; doi:10.4161/auto.1.1.1536. 4. Koren I, Reem E, Kimchi A. Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process. Autophagy 2010; 6:1179-80; PMID:20818178; doi:10.4161/auto.6.8.13338.
5. Koren I, Reem E, Kimchi A. DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 2010; 20:1093-8; PMID:20537536; doi:10.1016/j. cub.2010.04.041. 6. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010; 465:942-6; PMID:20526321; doi:10.1038/nature09076. 7. Shin C-S, Huh W-K. Bidirectional regulation between TORC1 and autophagy in Saccharomyces cerevisiae. Autophagy 2011; 7:854-62; PMID: 21490424.
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Autophagy
Volume 7 Issue 8
