Fig. 3a–c.

Regulation of autophagy induction in yeast and mammalian cells. a Regulatory complex for autophagy induction in yeast. In yeast, autophagy is mainly a starvation response, and Tor kinase complex 1 (TORC1) regulates the induction of autophagy upon sensing the nutrient conditions. Atg1 kinase, which is essential for both autophagy and the Cvt pathway, forms a putative complex with several Atg proteins that are primarily required for autophagy (in green) or the Cvt pathway (in purple). Under nutrient-rich conditions, TORC1 is active and Atg13 is highly phosphorylated, and this hyperphosphorylated Atg13 has a lower affinity for Atg1 and Atg17. Upon inactivation of TORC1 by nutrient starvation, Atg13 is rapidly and partially dephosphorylated, leading to a higher affinity for Atg1 and Atg17. The formation of the Atg1–Atg13–Atg17 ternary complex allows the activation of Atg1 kinase activity, which may regulate the switch between autophagy and the Cvt pathway in response to environmental changes. The function of additional components of the putative complex depicted here, including Atg20, Atg24, Atg29, Atg31 and Vac8, are not known. Atg11 may function in part as a scaffold protein. This figure is modified from Fig. 2 of Yorimitsu and Klionsky (2005b) b Multiple nutrient-sensing kinase signaling pathways converge on autophagy in yeast. TORC1 plays a major role in the regulation of autophagy. Ras is active under nutrient-rich conditions and allows the activation of PKA, which inhibits autophagy. The PKA and Sch9 signaling pathways cooperatively regulate the induction of autophagy in parallel with Tor, although Sch9 is also a direct substrate of TORC1. The eIF2α kinase signaling pathway positively regulates autophagy, and Gcn2 might be another target of TORC1. Snf1 and Pho85 are additional positive and negative regulatory components, respectively, of autophagy in yeast. c Regulation of autophagy in mammalian cells. mTor activation depends on several inputs, including nutrients (amino acids), energy (ATP) and growth factor (insulin/IGF). In response to insulin receptor stimulation, a class I phosphoinositide 3-kinase (PtdIns3K) is activated and generates PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ at the plasma membrane, and the latter two activate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB)/Akt. PKB phosphorylates and inhibits the GTPase-activating protein complex TSC1–TSC2, leading to the stabilization of Rheb-GTP, which stimulates mTor, causing inhibition of autophagy. PTEN, a 3′-phosphoinositide phosphatase, antagonizes PKB and has a stimulatory effect on autophagy. Both mTor and PDK1 stimulate p70S6 kinase (p70S6K). In one model, under nutrient-rich conditions, activation of S6K directly stimulates autophagy, or it is stimulated indirectly through inhibition of PtdIns3K, allowing a basal level of autophagy for homeostatic purposes. Under starvation conditions, inhibition of mTor prevents further activation of S6K, which limits and prevents excessive autophagy. Both ATP and amino acid deprivation result in mTor inactivation independent of the insulin signaling pathway. Amino acids activate mTor via inhibition of the TSC1–TSC2 complex or are sensed by mTor directly. Energy stress causes activation of the LKB1–AMPK pathway, which inhibits mTor by activating TSC1–TSC2. AMPK phosphorylates and stabilizes p27, a cyclin-kinase inhibitor, leading to activation of autophagy. An antiapoptotic protein, Bcl-2, associates with Beclin 1, the mammalian homolog of Atg6, and inhibits a class III PtdIns3K complex, whereas the latter serves a stimulatory role in autophagy. Also shown is the notion that Atg1 overexpression negatively feeds back on Tor activity in Drosophila