Key amongst these regulatory factors are the small GTPase Rheb, which directly associates with TOR to stimulate its signaling activity, and the TSC1 and TSC2 proteins, which together inhibit Rheb through the GAP activity of TSC2. Signals that influence autophagy independently of TOR are also considered, with the goal of considering how specific steps of autophagy induction can be influenced by distinct molecular cues.įollowing the pioneering studies in the early 1990s that identified the TOR kinases as targets of rapamycin in yeast, experiments in mammalian cells and other model systems have defined several important regulatory steps and components that link TOR activity to upstream signals. The purpose of this review is to provide a summary of recent insights into the events upstream of TOR that regulate its function, and to discuss new developments in our understanding of how TOR interacts with the core set of proteins that directly control autophagosome formation and maturation. Control of autophagy by TORC1 signaling is largely responsible for the potent effect of starvation as an autophagy inducer. This signaling complex includes TOR, the scaffolding protein Raptor, and additional proteins that also function with TOR in a second, rapamycin-insensitive complex not involved in autophagy (reviewed in ). The drug rapamycin induces autophagy in a wide variety of cell types and species by inhibiting the activity of TOR as part of the multi-component TOR Complex 1 (TORC1). TOR kinases are central regulators of multiple cellular responses to nutrient and growth factor signaling, including autophagy. Both insufficient and excessive levels of autophagy have been shown to impact human health at multiple levels, and therefore understanding the cellular mechanisms that regulate this process is an important goal (reviewed in ). In response to starvation and other stresses, activation of autophagy can generate an internal source of nutrients that promotes survival in the absence of externally supplied nutrition. Autophagy normally proceeds at a low, basal rate, playing a key role in the homeostatic clearance of old or damaged organelles and proteins. Chief amongst these responses is autophagy, a process whereby cytoplasmic constituents are engulfed within specialized double-membrane vesicles known as autophagosomes, for subsequent delivery to and degradation within the lysosome. Increasing evidence is pointing to an important role for both positive and negative feedback loops in controlling this pathway, leading to an emerging view that TOR signaling not only regulates autophagy but is also highly sensitive to cellular rates of autophagy and other TOR-dependent processes.Įukaryotic cells have evolved a number of defense mechanisms that allow survival in the face of environmental insults such as nutrient depletion, oxidative damage and conditions that disrupt protein folding. In some cases these signals appear to have been spliced into the core TOR pathway, whereas others are able to bypass the control mechanisms regulated by TOR. In addition, a variety of signals, stressors and pharmacological agents that induce autophagy independent of nutrient conditions have been identified. Recent studies have begun to reveal how TOR activity is regulated in response to nutritional cues, and are shedding new light on the mechanisms by which TOR controls the autophagic machinery. The target of rapamycin (TOR) pathway is major conduit for such signals, and in most cell types TOR activity is necessary and sufficient to suppress autophagy under favorable growth conditions. Induction of autophagy in response to starvation is a highly conserved ability of eukaryotic cells, indicating a critical and ancient role of this process in adapting to nutrient conditions.
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