TOR-dependent control of autophagy: biting the hand that feeds - PubMed (original) (raw)

Review

TOR-dependent control of autophagy: biting the hand that feeds

Thomas P Neufeld. Curr Opin Cell Biol. 2010 Apr.

Abstract

Induction of autophagy in response to starvation is a highly conserved ability of eukaryotic cells, indicating a crucial and ancient role of this process in adapting to nutrient conditions. 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. 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. In addition, a variety of signals, stressors and pharmacological agents that induce autophagy independent of nutrient conditions have been identified. 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. 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.

Copyright 2009 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Mechanisms of signaling redundancy in the TOR pathway

Multiple inputs regulate activity of the TOR/Raptor/Lst8 complex (TORC1) through redundant upstream signaling pathways. Interactions leading to activation of a downstream component are indicated by arrows; those that inhibit are indicated by a bar. The canonical Tsc1/Tsc2-dependent TOR pathway is indicated by the blue lines. Recently described Tsc1/Tsc2-independent signals are shown in red. Decreases in cellular energy level (ATP/AMP ratio) cause phosphorylation of Raptor by the AMP-dependent protein kinase, leading to 14-3-3 mediated inhibition of TORC1 [20]. In response to insulin and other growth factors, Akt phosphorylates and inactivates PRAS40 (not shown), an inhibitor of TORC1 [–24]. Decreases in cellular oxygen levels lead to increased expression of hypoxia-induced genes, including Bnip3, which binds and inhibits the small GTPase Rheb [27].

Figure 2

Figure 2. Mechanisms of feedback signaling in the TOR pathway

(a) Negative feedback mechanisms that limit activation of autophagy are shown in red. Protein degradation within the autolysosome raises the intracellular levels of amino acids, leading to activation of TOR through the RagA/RagC small GTPases and other nutrient signaling pathways. TOR activity is self-limited through an S6K-mediated inhibition of IRS1 (not shown), an essential component in the insulin/PI3K/Akt pathway upstream of Rheb. S6K is also involved in a self-limiting pathway in autophagy induction downstream of TOR, probably through its function in protein synthesis. Inhibition of TOR leads to both activation of Atg1 and inactivation of S6K; both of these kinases play positive roles in starvation-induced autophagy. (b) Feed-forward mechanisms in TOR signaling, indicated by green lines, may lead to amplification and stabilization of initially modest changes in TOR activity. DEPTOR, PRAS40 and Atg1 are each inhibited by TOR mediated phosphorylation and in turn inhibit TOR activity. In yeast, TOR mediates activation of Tap42, which leads to downregulation of the phosphatase Sit4 and decreased activity of the Tap42 inhibitor Tip41, resulting in further activation of Tap42.

Similar articles

Cited by

References

    1. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–1075. - PMC - PubMed
    1. He C, Klionsky DJ. Regulation Mechanisms and Signaling Pathways of Autophagy. Annu Rev Genet. 2009 - PMC - PubMed
    1. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007;12:487–502. - PubMed
    1. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. 2009;296:E592–602. - PMC - PubMed
    1. Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem. 2005;280:18717–18727. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources