Editors' ChoiceCell Biology

Autophagy and Growth

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Science's STKE  17 Aug 2004:
Vol. 2004, Issue 246, pp. tw291
DOI: 10.1126/stke.2462004tw291

During periods of starvation, a eukaryotic cell can gain nutrients by digesting intracellular organelles and macromolecules present in the cytosol through a process called autophagy. Cytoplasmic contents are sequestered into autophagosomes that eventually fuse with degradative lysosomes. When nutrients are plentiful, a nutrient-sensing pathway controlled by the serine-threonine kinase TOR suppresses this self-consumption process. Similarly, the insulin-phosphoinositide 3-kinase (PI3K) pathway that acts upstream of TOR can also block autophagy. Because TOR and PI3K both activate cell growth as well, it has been suggested that induction of autophagy may affect cell growth. Induction of autophagy has been associated with reduced cell growth. Furthermore, in Drosophila, starvation inactivates TOR and PI3K, and disruption of either molecule reduces larval growth. Scott et al. suggest that activation of cell growth and inhibition of autophagy are controlled by two separate branches of the TOR pathway. They demonstrate that in Drosophila larvae, starvation-induced autophagy requires inactivation of TOR. In the absence of a functional TOR pathway, flies exhibited increased autophagy in fat body cells. This was associated with growth arrest of TOR mutants, observed in either TOR-null flies or mutant flies engineered to express altered forms of TOR regulatory molecules. In contrast, mutations in other growth regulators did not increase autophagy, indicating that reduced cell growth in general does not trigger the process. However, lack of the functional ribosomal protein S6 kinase (S6K), a downstream effector of TOR that regulates cell growth, did not induce autophagy, indicating that growth and autophagy are separately controlled outputs of TOR signaling. RNA interference-mediated knockdown of the expression of ATG genes, whose homologs in yeast have been implicated in autophagy control, indicated their requirement for the autophagy starvation response in Drosophila. However, loss of ATG genes arrested cell growth and development of TOR-defective larvae. The data suggest that induction of autophagy, resulting from the loss of TOR signaling, is required for cells to maintain their growth in low-nutrient conditions. Rusten et al. also observed that starvation and inhibition of TOR or PI3K induced autophagy in the Drosophila fat body and that the developmental hormone ecdysone promotes autophagy by down-regulating PI3K signaling. Inhibition of ecdysone signaling by expression of dominant-negative receptors or activation of the PI3K pathway blocked autophagy during late larval development. The study suggests that developmentally controlled changes in tissues and organs involves programmed autophagy.

R. C. Scott, O. Schuldiner, T. P. Neufeld, Role and regulation of starvation-induced autophagy in the Drosophila fat body. Devel. Cell 7, 167-178 (2004). [Online Journal]

T. E. Rusten, K. Lindmo, G. Juhasz, M. Sass, P. O. Seglen, A. Brech, H. Stenmark, Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Devel. Cell 7, 179-192 (2004). [Online Journal]

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