Nutrient-dependent regulation of autophagy through the target of rapamycin pathway

Abstract

In response to nutrient deficiency, eukaryotic cells activate macroautophagy, a degradative process in which proteins, organelles and cytoplasm are engulfed within unique vesicles called autophagosomes. Fusion of these vesicles with the endolysosomal compartment leads to breakdown of the sequestered material into amino acids and other simple molecules, which can be used as nutrient sources during periods of starvation. This process is driven by a group of autophagy-related (Atg) proteins, and is suppressed by TOR (target of rapamycin) signalling under favourable conditions. Several distinct kinase complexes have been implicated in autophagic signalling downstream of TOR. In yeast, TOR is known to control autophagosome formation in part through a multiprotein complex containing the serine/threonine protein kinase Atg1. Recent work in Drosophila and mammalian systems suggests that this complex and its regulation by TOR are conserved in higher eukaryotes, and that Atg1 has accrued additional functions including feedback regulation of TOR itself. TOR and Atg1 also control the activity of a second kinase complex containing Atg6/Beclin 1, Vps (vacuolar protein sorting) 15 and the class III PI3K (phosphoinositide 3-kinase) Vps34. During autophagy induction, Vps34 activity is mobilized from an early endosomal compartment to nascent autophagic membranes, in a TOR- and Atg1-responsive manner. Finally, the well-known TOR substrate S6K (p70 ribosomal protein S6 kinase) has been shown to play a positive role in autophagy, which may serve to limit levels of autophagy under conditions of continuously low TOR activity. Further insight into these TOR-dependent control mechanisms may support development of autophagy-based therapies for a number of pathological conditions.

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

“…In most of the cell lines studied in vitro, rapamycin and rapalogs induce a partial growth inhibition and limited autophagy (32). mTORC1 has been shown to control autophagy by direct and indirect mechanisms (32,33). Recently, OSI-027, but not rapamycin, has been shown to profoundly stimulate autophagy in K562 leukemic cells and RCC cell lines (34,35).…”

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

“…Finally, TORC1 is also a known negative regulator of autophagy (Chang et al 2009). TORC1 activity controls the phosphorylation status of Atg13.…”

Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

“…Conversely, insufficient levels of these factors, or signals of cell stress, blunt mTORC1 action to maintain cellular biosynthetic rates appropriate for suboptimal cellular conditions (3,21,22). Reduced mTORC1 signaling also promotes macroautophagy, a degradative process that enhances cell survival in the face of decreased nutrient availability via the breakdown of cell constituents into amino acids and other small molecules (23). TORC1 in yeast and mammals also promotes "ribosome biogenesis," a process whereby mTORC1 increases the transcription of ribosomal RNAs and proteins to augment cellular protein biosynthetic capacity (24).…”