2008 Landes Bioscience. Do not distribute. The role of TOR in autophagy regulation from yeast to plants and mammals. Review.

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1 [Autophagy 4:7, ; 1 October 2008]; 2008 Landes Bioscience Review The role of TOR in autophagy regulation from yeast to plants and mammals Sandra Díaz-Troya, María Esther Pérez-Pérez, Francisco J. Florencio and José L. Crespo* Instituto de Bioquímica Vegetal y Fotosíntesis; Consejo Superior de Investigaciones Científicas (CSIC); Seville Spain Key words: TOR signaling, rapamycin, cell growth, kinase, autophagy, ATG genes, plants, algae The target of rapamycin (TOR) is a conserved Ser/Thr kinase that controls cell growth by activating an array of anabolic processes including protein synthesis, transcription and ribosome biogenesis, and by inhibiting catabolic processes such as mrna degradation and autophagy. Control of autophagy by TOR occurs primarily at the induction step, and involves activation of the ATG1 kinase, a conserved component of the autophagic machinery. A substantial number of genes participating in autophagy have been originally identified in yeast. Most of these genes have mammalian homologues and many have apparent homologues in plants, indicating that autophagy is conserved among eukaryotes. The recent identification of TOR as a key element in cell growth control in plants and algae opens the way for future studies to investigate whether this signaling pathway may also control autophagy in photosynthetic organisms. Introduction Cells have developed sophisticated mechanisms for perceiving and transmitting appropriate growth stimuli and tightly couple nutrient availability to cellular growth control (where cell growth refers to an increase in cell mass). An increasing body of evidence points to the target of rapamycin (TOR) kinase as an essential protein that integrates nutritional inputs to regulate cell growth in all eukaryotes (reviewed in ref. 1). TOR was originally identified by genetic screens in the budding yeast S. cerevisiae and subsequently in other organisms including fungi, mammals, flies and worms (reviewed in refs. 2 and 3). More recently, TOR has been described in plants and algae, indicating that this kinase is also conserved in photosynthetic organisms. 4,5 TOR is present as a single gene in most eukaryotes, although certain organisms such as yeast and other fungi appear to contain two TOR genes. The TOR kinases are large (about 270 kda) proteins that assemble into two structurally and functionally distinct multisubunit complexes termed TORC1 (TOR complex 1) and TORC2. 1 *Correspondence to: José L. Crespo; Instituto de Bioquímica Vegetal y Fotosíntesis; Consejo Superior de Investigaciones Científicas (CSIC); Avda. Américo Vespucio, 49; Seville Spain; Tel.: ; Fax: ; crespo@ ibvf.csic.es The TOR signaling pathway controls cell growth by promoting a number of anabolic processes including protein synthesis, transcription and ribosome biogenesis, and by antagonizing catabolic processes such as mrna degradation and autophagy. 1 The control of these and other important cellular processes allows TOR to spatially and temporally govern cell growth. 6 Genetic and biochemical studies in yeast demonstrated that TOR regulates these two distinct aspects of cell growth by two separate signaling pathways defined by TORC1 and TORC2, respectively. 6,7 As discussed below, TORC1 modulates temporal cell growth whereas TORC2 controls spatial cell growth. Under TOR-inactivating conditions, i.e., nutrient limitation, cells undergo a catabolic membrane-trafficking process known as macroautophagy (hereafter referred to as autophagy). During this process, a large number of cytosolic components are non-selectively enclosed within a double-membrane structure (autophagosome) and delivered to the vacuole for degradation to recycle needed nutrients or degrade toxic components (reviewed in ref. 8). Autophagy is conserved among yeast, animal and plant cells, indicating that many of the structural and regulatory components of this cellular process must be conserved. Accordingly, genomic approaches have revealed that a significant number of autophagy-related (ATG) genes that participate in the activation and regulation of this process as well as autophagosome formation are evolutionarily conserved from yeast to plants. 9,10 Studies performed mostly in yeast demonstrate that the TOR signaling pathway plays an important role in autophagy activation, 11 and it has been recently proposed that TOR may also control autophagy in photosynthetic organisms. 4,10 In this review, we give a brief overview of TOR signaling in lower and higher eukaryotes, with special emphasis in photosynthetic organisms, and discuss the role of TOR in autophagy. General Aspects of TOR Signaling in Non-Photosynthetic Eukaryotes Two TOR complexes. The TOR proteins were identified in budding yeasts as the targets of the immunosuppressive and anticancer drug rapamycin. 12 However, to achieve its inhibitory effect, rapamycin must first form a complex with the immunophilin FKBP12 (FK506 binding protein), and the FKBP12-rapamycin complex then binds and inhibits TOR. Genetic studies developed in yeast showed that TOR performs at least two major functions because not all of its functions are sensitive to rapamycin. 6,13-15 These two separable signaling branches regulate numerous aspects of Submitted: 04/16/08; Revised: 06/24/08; Accepted: 07/08/08 Previously published online as an Autophagy E-publication: Autophagy 851

2 cell growth and metabolism, and are conserved through evolution. The differential sensitivity of TOR to rapamycin and the signaling specificity in these two branches were explained by the finding that TOR resides in two distinct multiprotein complexes, termed TORC1 and TORC2, which modulate each signaling branch. 7 In yeast, TORC1 contains either TOR1 or TOR2, KOG1, TCO89 and LST8, whereas TORC2 includes TOR2 (but not TOR1), LST8, BIT61, AVO1, AVO2 and AVO3. 7,16,17 Similarly, mammalian TOR (mtor) associates with raptor (homologue of yeast KOG1) and mlst8 to constitute mtorc1, while mtorc2 consists of mlst8, rictor (homologue of yeast AVO3), SIN1 (homologue of yeast AVO1) and mtor. 7,18-25 The similar composition of TORCs in widely divergent kingdoms such as metazoans and fungi suggests these complexes are broadly conserved among all eukaryotes. KOG1/raptor is a large protein (about 150 kda) that contains a conserved N-terminal domain followed by four HEAT repeats and seven carboxy-terminal WD40 repeats and is found exclusively in TORC1. 7,19,22 Studies performed in yeast and mammals indicate that raptor is an essential protein that acts positively in TORC1, functioning as a scaffold protein that couples TOR to its targets. 7,19 LST8 (also known as G beta-like or GβL in mammals) is composed entirely of seven WD40 repeats and it is the only TORpartner found in both TORC1 and TORC2. In yeast, LST8 is required for amino acid permease transport from the Golgi apparatus to the cell surface, 26,27 and localizes as a peripheral membrane protein to endosomal or Golgi membranes. 17,26 LST8 binds to the kinase domain of yeast and mammalian TORs, and although it is still unclear how LST8 can promote TOR kinase activity, it has been proposed that LST8 may stabilize the TOR kinase domain. 23,28 In agreement with this hypothesis, it has been demonstrated that LST8 is required for TORC2 stability and in vitro kinase activity. 28 Recent studies performed with mlst8 null mice embryos support this model. mlst8 functions to maintain a stable association between rictor and mtor, which is required for proper TORC2 signaling. 29 Interestingly, mlst8 appears to be dispensable for mtorc1 activity based on the finding that mlst8 is not required to maintain the raptor-mtor interaction. 29 However, these data seem to contravene previous studies in yeast and mammalian cells which indicate that LST8 is required for TORC1 signaling. 21,23,26 To resolve these discrepancies, an understanding of the molecular mechanisms by which LST8 controls TOR activity is required. The conserved module in TORC2 contains a TOR kinase, LST8, AVO1/SIN1 and AVO3/rictor. The AVOs were originally identified in yeast as TOR2-interacting proteins, 7,17 and subsequently in mammalian cells as components of mtorc2. 7,18,20,21,24,25 Yeast and mammalian AVOs appear to act positively on TORC2, but the specific functions of these proteins remain to be determined. Yeast AVO1 and AVO3 bind to the amino-terminal part of TOR2 and are required for TORC2 stability. 28 Mutations in TOR2 or reduced expression of AVO1 result in a similar actin depolarization phenotype, indicating that AVO1 is involved in the control of actin polymerization. 7,30-32 In mammals, SIN1 deletion leads to loss of TORC2 complex formation and kinase activity. 18,20,25 Consistent with the phenotype observed in yeast upon TORC2 disruption, knockdown of mtor or rictor in mammalian cells also results in loss of actin polymerization and cell spreading, suggesting that TORC2 controls the actin cytoskeleton. 21,24 TOR complexes have also been identified in the fission yeast Schizosaccharomyces pombe. Similar to budding yeast, fission yeast has two TOR proteins, namely Tor1 and Tor2, which integrate into two distinct TOR complexes. Based on sequence alignment, Tor2 in S. pombe corresponds to TOR1 in S. cerevisiae as the TOR that forms TORC1, whereas S. pombe Tor1 corresponds to S. cerevisiae TOR Homologues to KOG1/raptor, LST8, AVO1/SIN1 and AVO3/rictor have been identified in fission yeast as the Mip1, Wat1, Sin1 and Ste20 proteins, respectively (reviewed in ref. 34). Immunoprecipitation studies indicated that, similar to budding yeast TORCs, fission yeast TORC1 comprises Tor2, Mip1 and Wat1 while TORC2 includes Tor1, Sin1, Ste20 and Wat1. 34 However, S. pombe TOR signaling differs from the budding yeast and mammalian TOR systems in two aspects: first, inhibition of TOR signaling by rapamycin has no effect on cell growth, 37 and second, both TORC1 and TORC2 appear to be rapamycin sensitive. 38 These special features of fission yeast make S. pombe as an attractive system to investigate the function of TOR. The cellular localization of yeast and mammalian TORCs has been investigated by different techniques, including subcellular fractionation, indirect immunofluorescence (IF) microscopy, and immunoelectron microscopy. Albeit with significant discrepancies, these studies all agree that TORCs are primarily membrane associated. Yeast TORC1 has been reported to be associated to the plasma, vacuolar and endosomal membranes, although a recent study revealed that at least part of TOR1 shuttles in and out of the nucleus. 17,39-42 Localization of TOR in mammalian cells is also controversial since mtor has been reported to be associated with mitochondrial, endoplasmic reticulum and Golgi apparatus membranes, as well as in the nucleus The functional significance of TORCs association with multiple membranes is at present unknown. TORC1 readouts. TORC1 functions are sensitive to FKBP12- rapamycin in both yeast and mammals. All TORC1 components can be pulled down by the FKBP12-rapamycin complex in yeast cells, indicating that FKBP12-rapamycin does not affect TORC1 stability. 7 These findings implicate that rapamycin does not inhibit TORC1 signaling through disruption of this complex. In contrast, several groups have observed that rapamycin inhibits binding of raptor to mtor, 19,22,46 indicating that the inhibitory action of rapamycin on mtorc1 signaling is likely due to the ability of the rapamycin-fkbp12 complex to interfere with the proper interaction of mtor to raptor. However, it has been reported that rapamycin does not affect mtorc1 stability. 24,47 Thus, the molecular mechanism of rapamycin-fkbp12 inhibition of TORC1 remains to be defined. As mentioned above, TORC1 mediates temporal control of cell growth. TOR is active under favorable growth conditions, and promotes ribosome biogenesis, translation initiation, and nutrient import. However, nutrient starvation, rapamycin treatment or TOR depletion dramatically downregulates general protein synthesis, activates autophagy and a number of stress-responsive transcription factors. 2,3 In mammals, TORC1 controls translation initiation by regulating the cap-binding translation initiation factor eif4e and the AGC protein S6 kinase (S6K). TORC1 indirectly regulates eif4e by phosphorylating the eif4e-binding proteins, 4E-BPs. 2,3 The 40S ribosomal phosphoprotein S6 has been proposed to affect the 852 Autophagy 2008; Vol. 4 Issue 7

3 translation of mrna transcripts containing a 5'-terminal oligopyrimidine tract (5'-TOP) motif. Most 5' TOP mrnas encode components of the translational apparatus, such as ribosomal proteins and elongation factors. 48 In the presence of amino acids, mtorc1 promotes phosphorylation of S6 through activation of S6K. It has been widely accepted that phosphorylation of S6 increases the affinity of ribosomes to TOP mrnas and thus facilitates the translation initiation of this class of mrnas. However, recent studies with cultured cells have shown that translation activation of TOP mrnas does not require S6 phosphorylation (reviewed in ref. 52). Thus, the exact role of the TOR kinase in the translational control of TOP mrnas remains to be fully established. Regulation of translation initiation by TORC1 appears to be conserved in lower eukaryotes. In yeast, TORC1 may also maintain translation initiation via eif4e 53 and regulation of EAP1, a putative 4E-BP protein, 54 and phosphorylation of SCH9, an AGC protein kinase with structural similarity to S6K that has been recently reported to regulate translation initiation and phosphorylate ribosomal protein S6. 42 TOR is a key regulator of ribosomal gene transcription. In yeast cells, TORC1 signaling regulates ribosome biogenesis at both the transcriptional and translational levels. Inhibition of TORC1 by rapamycin treatment or nutrient starvation leads to a downregulation of transcription of ribosomal protein (RP) mrnas by polymerase II 55 as well as transcription of rrna and trna by polymerases I and III. 55,56 TORC1 also controls processing of at least the 35S precursor rrna. 55 Recent studies indicate that TORC1 controls RP gene expression by regulating the cellular localization FHL1 and SFP1, two transcription factors that bind and activate RP promoters. 3,57 In mammalian cells, TORC1 regulates the abundance of ribosomal proteins and other components of the translation machinery, such as the poly(a)-binding protein, by promoting translation of 5' TOP mrnas through a S6K-independent pathway 49,52 (see above). Control of gene expression at the level of transcription represents an important branch of TORC1 signaling, as revealed by genomewide expression studies of rapamycin-treated yeast cells The most striking sets of genes affected by rapamycin are those involved in the uptake and assimilation of alternative nitrogen sources. TORC1 controls the expression of nutrient-regulated genes by sequestering several nutrient-responsive transcription factors in the cytoplasm. TORC1 promotes cytoplasmic retention of (i) the GATA transcription factors GLN3 and GAT1, 61 two major activators of nitrogen-responsive genes, 62 (ii) the partially redundant zincfinger transcription factors MSN2 and MSN4, 61 which respond to different types of cellular stresses, including carbon source limitation, and (iii) the heterodimeric bhlh/zip transcription factor complex composed of RTG1 and RTG3, 63 a central element of the retrograde response (mitochondria-to-nucleus) pathway. 64 Microarray experiments on rapamycin-treated mammalian cells indicate that mtorc1 signaling also controls transcription of many genes, particularly genes involved in metabolic and biosynthetic pathways. 65 mtorc1 may control transcriptional programs through regulation of URI, an evolutionarily conserved protein that interacts with all three RNA polymerases and whose phosphorylation state is rapamycin sensitive. 66 TORC1 signaling plays a prominent role in regulation of amino acid permease activity. Studies in yeast demonstrated that TORC1 inversely controls sorting of high- and low-affinity permeases. Inhibition of TORC1 by rapamycin or nitrogen starvation results in ubiquitination and vacuole targeting of high-affinity permeases TORC1 may regulate sorting of these transporters via the protein kinase NPR1, a phosphoprotein whose phosphorylation state (and presumably activity) is controlled by TORC1 in response to the nitrogen source. 69 In contrast to the downregulation of high-affinity permeases, nitrogen starvation or rapamycin treatment also leads to a rapid sorting of low-affinity, broad-specificity transporters to the cell surface. Mammalian TORC1 may play a similar role in regulating the traffic of nutrient permeases through the membrane in higher eukaryotes. It has been proposed that the mtor pathway is involved in the rapid mobilization of the glucose transporter GLUT4 to a highly insulin-responsive compartment upon insulin stimulation. 70 Growth factors appear to stimulate nutrient uptake by positively regulating mtorc1 signaling downstream of the Akt/PKB (see below). 71 TORC2 readouts. Unlike TORC1, TORC2 regulates cell growth in a rapamycin-insensitive manner. To date, there is no equivalent to rapamycin with which to target TORC2. Therefore, the readouts downstream of TORC2 are much less well characterized than those of TORC1. The first and best characterized function of TORC2 is the control of cell polarity by regulation of actin cytoskeleton polarization. Disruption of TORC2 results in depolarization of actin cytoskeleton in both yeast and mammals, indicating that this TORC2 readout is conserved through evolution. 7,21,24,32 In yeast, TORC2 signaling to the actin cytoskeleton is mediated by activation of the small GTPase RHO1 via the exchange factor ROM2. RHO1, in turn, signals to the actin cytoskeleton via its direct effector PKC1 and a PKC1-activated MAP kinase cascade. 3,31 How TORC2 signals to ROM2 remains unknown. However, the recent identification of the AGC kinase YPK2 and the PH domain-containing proteins SLM1/2 as direct substrates of TORC2 has shed light on the understanding of this signaling pathway to the actin cytoskeleton, since mutations on YPK2 or SLM1/2 result in perturbation of the actin cytoskeleton In addition to the control of actin cytoskeleton, TORC2 has been recently reported to control de novo ceramide synthesis in yeast by activating YPK2. 75 In mammals, TORC2 also signals to the actin cytoskeleton through a signaling pathway that involves PKCα and the small GTPases Rho and Rac, 21,24 although the direct targets of mtorc2 that mediate signaling to the actin cytoskeleton remain unknown. Recent studies indicate that TORC2 also modulates actin polymerization and cell polarity by processes that may involve Akt/PKB, 76 another member of the AGC protein kinase family that participates in the regulation of cell proliferation, survival, metabolism and transcription. Regulation of TOR. In yeast, inhibition of TORC1 signaling by rapamycin treatment remarkably resembles the cellular response to nitrogen or carbon starvation, indicating that TORC1 responds at least to nutrient availability. 2,3 However, the specific nitrogen or carbon metabolites that act upstream of TORC1 are presently unknown. It has been proposed that TORC1 signaling, or at least a specific subset of the TORC1 pathway, responds to glutamine, suggesting that this amino acid is a particularly important indicator of nutrient status. 77 Indeed, glutamine is a preferred nitrogen source, controls carbon metabolism via the tricarboxylic acid cycle, and Autophagy 853

4 functions as an immediate precursor for the biosynthesis of other amino acids, nucleotides and other nitrogencontaining molecules. 62 The molecular mechanism by which glutamine and/or other metabolites control TOR activity is unknown. Recent evidence suggests that the newly discovered, vacuolar membrane-associated EGO (exit from rapamycin-induced growth-arrest) protein complex could positively act on TOR signaling by transmitting critical nutrient signals to TORC1. 78 In mammals, mtor has been proposed to act as a multiple-channel sensor for a variety of upstream signals. mtor activity can be modulated by growth factors, including insulin, amino acids such as leucine and glutamine, intracellular levels of ATP, phosphatidic acid and inorganic polyphosphates. 1 Several lines of evidence indicate that both the mtorc1 pathway and PI3K-Akt/PKB signaling are involved in the regulation of the phosphorylation of S6K and 4EBP1 in response to insulin stimulation. Akt has been shown to act upstream of TORC1 and indirectly stimulates TORC1 activity (Fig. 1). Insulin induces Akt-mediated inhibition of the TSC1-TSC2 complex which negatively regulates the small GTPase Rheb, an mtorc1 interacting protein that activates mtor. 1 Rheb appears to regulate mtorc1 through FKBP38, a member of the FKBP family that binds to and inhibits mtor activity. Rheb interacts directly with FKBP38 and prevents its association with mtor in a GTP-dependent manner. 79 The relationship between TORC1 and the PI3K-Akt pathway is complex. On the one hand, it has been recently demonstrated that mtorc2, but not mtorc1, is able to phosphorylate and activate Akt. 76 Since Akt activates mtorc1, mtorc2 could indirectly activate mtorc1. However, several lines of evidence suggest that mtorc2 activates a pool of Akt that is not upstream of mtorc1. 21,24 On the other hand, activation of TORC1 by insulin results in a negative feedback loop that inhibits PI3K signaling via the TORC1 downstream effector S6K, which inhibits the insulin receptor substrate-1. 1 Amino acids also regulate mtorc1 signaling but there is no consensus about the mechanism by which amino acid availability is communicated to mtorc1. It has been proposed that amino acids activate mtorc1 via inhibition of TSC1-TSC2 or, alternatively, via stimulation of Rheb, 1 while other studies indicate that amino acids stimulate mtorc1 activation through the class III PI3K hvps34 independently of TSC1-TSC2 and Rheb However, control of TOR signaling by VPS34 might not be evolutionarily conserved since in contrast to the case of cultured mammalian cells, Vps34 does not act upstream of TOR in Drosophila. 83 Interestingly, the Rag family of small GTPases has recently been identified as activators of TORC1 in response to amino acids signals in both mammals and flies. 84,85 The Rag proteins appear to interact with mtorc1 in an amino acid-sensitive manner and are necessary for the activation of the mtorc1 pathway by amino acids. Similarly, genetic studies in Drosophila also show that the Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Figure 1. Control of autophagy by the TOR signaling network in metazoans. mtorc1 receives inputs from intracellular and extracellular stimuli, including nutrients (amino acids) and growth factors (insulin). Amino acids may activate the GTPase Rheb which positively regulates mtorc1 while the growth factor signal is transduced to the tumor suppressor complex TSC1/TSC2 via the insulin signaling pathway. TSC1/TSC2 negatively regulates mtorc1 by inactivating Rheb. Once activated, mtorc1 inhibits autophagy by acting on the ATG1 complex. Studies performed in Drosophila indicate that ATG1 negatively feeds back on TOR signaling by an unknown mechanism. S6K may contribute to the basal activity of autophagy via its feedback inhibition of the PI3K-dependent signaling pathway. Green arrows represent activation, whereas red bars represent inhibition. Dashed lines refer to potential interactions. Control of Autophagy by TOR In response to nutrient limitation, cells undergo a catabolic membrane-trafficking process known as autophagy. During this process, a large number of cytoplasmic components are non-selectively enclosed within a double-membrane structure (autophagosome) and delivered to the vacuole/lysosome for degradation and recycling (reviewed in refs. 8, 86 and 87). Genetic and morphological analyses reveal that the degradative process of autophagy shares mechanistic components with the cytoplasm-to-vacuole targeting (Cvt) pathway The Cvt pathway is biosynthetic, and ensures the delivery of resident hydrolases, amino-peptidase I (Ape1), and α-mannosidase to the vacuole However, these two processes 854 Autophagy 2008; Vol. 4 Issue 7

5 differ in many aspects, including vesicle size. 95 The biogenesis and consumption of both autophagosomes and Cvt vesicles can be divided into four steps: 86 (i) induction of vesicle formation, which is triggered in response to different cellular signals for autophagosomes and Cvt vesicles; autophagosomes are induced by starvation whereas binding of precursor Ape1 to its receptor appears to be the signal that induces Cvt vesicles; (ii) vesicle formation and completion, which starts with the engulfment of the selected cargo by a membrane, and finishes with the fusion of the extremities of the surrounding membrane to generate a double-membrane vesicle; (iii) docking and fusion of autophagosomes and Cvt vesicles to the vacuole membrane; this process is likely mediated by a fusion machinery similar to the one used by Golgi- and endosome-derived vesicles to fuse with vacuoles, which includes SNARE proteins, a rab-gtpase, and a class C vps protein complex; (iv) vesicle breakdown, which takes place upon fusion of the autophagosome or Cvt vesicle with the vacuole and the subsequent release of the inner vesicle (called autophagic or Cvt bodies) into the vacuolar lumen. An increasing number of genes have been identified as essential components for the correct achievement of autophagy. Since the identification of the first autophagy-related gene, ATG1, by genetic screens for yeast autophagy mutants, 96 a total of thirty one ATG genes have already been reported. 97,98 Most of these genes have been genetically identified in yeast, and a significant number of them appear to be conserved in mammals and plants (see Table 1), strongly suggesting that autophagic processes are mechanistically conserved through evolution. Most of the genes required for autophagy are also required for the Cvt pathway. 8,86 Autophagy begins when the cell perceives a reduction in the availability of nutrients. The molecular mechanisms by which this starvation signal is transmitted to the autophagic machinery have been elucidated from studies performed in yeast. TOR has been identified as an essential component in the regulation of autophagy. Inactivation of TOR function by rapamycin induces autophagy even in rich nutrient conditions, indicating that TORC1 inhibits autophagy. 99 How does TORC1 control autophagy? TORC1 inactivation induces autophagy primarily at the level of autophagosome formation by negatively regulating the association between the Ser/Thr protein kinase ATG1 with ATG13, a regulatory subunit of ATG1, 100 (Fig. 2). The ATG1 kinase plays a pivotal role in the control of autophagy and its activity is required for the switch from the formation of Cvt vesicles to the formation of autophagosomes. 90,96 ATG1 and ATG13 appear to be the core of a regulatory system that controls conversion between Cvt transport and autophagy and whose activity is modulated by phosphorylation/dephosphorylation events and through interactions with factors specific for autophagy or the Cvt pathway. The role of the kinase activity of ATG1 in yeast is debated. Some studies found that ATG1 kinase activity is required for the Cvt pathway and autophagy. 100,101 However, it has also been reported that ATG1 kinase activity is required for the Cvt pathway but not for autophagy, suggesting a structural role for ATG1 in autophagy regulation. 102 ATG1 is part of a dynamic protein complex that includes ATG17, ATG11, ATG13 and VAC8, and the composition of this complex is regulated by the phosphorylation state of ATG1 and ATG13. Under nutrient-rich conditions, phosphorylated ATG1 interacts with ATG11 and ATG17, whereas phosphorylated ATG13 associates with VAC8. 100,103,104 The specific role of TORC1 in the regulation of autophagy is to maintain ATG13 in a phosphorylated form with low affinity for ATG1 and thereby to inhibit ATG1 activity. Inactivation of TORC1 by rapamycin treatment or nutrient starvation causes rapid dephosphorylation of ATG13, which increases the affinity of this protein for ATG1 and enhances ATG1 kinase activity. 100 ATG17 appears to participate in autophagosome formation likely by stabilizing the ATG1-ATG13 complex. 100 How TOR promotes ATG13 phosphorylation is currently unknown. The finding that mutations in the TORC1-controlled protein TAP42 have no effects on either ATG1 activity or autophagy induction suggests the ATG1-ATG13 interplay comprises a novel TORC1 signaling pathway regulating autophagy independent of TAP TOR inactivation also induces autophagy at the transcriptional level. Rapamycin treatment or nitrogen starvation causes translocation of GLN3 to the nucleus where it induces the transcription of nitrogen-regulated genes 61 (see above). Among these genes, some participate in autophagy and are part of the autophagic machinery. For instance, expression of ATG14, a component of the VPS34 complex essential for autophagy and the Cvt pathway, is tightly regulated by TOR through GLN Transcription of ATG8/AUT7, which is involved in the completion of transport of the Cvt and autophagy pathways, 106,107 is induced by nitrogen starvation presumably upon TOR-mediated activation of GLN3. 106,108 Microarray studies performed with rapamycin treated cells reveal that these and other autophagy genes such as ATG1, ATG3, ATG4, ATG5, ATG7, ATG12 and ATG13 are transcriptionally regulated by TOR. 58,109 In addition to TOR, autophagy is regulated by other protein kinases. Increased levels of Ras/PKA signaling activity resulted in a complete block to autophagy, indicating that this signaling pathway regulates an early step of the autophagy process. 110 Recently, it has been demonstrated that PKA directly phosphorylates ATG1 and regulates the association of this protein to the pre-autophagosomal structure. However, phosphorylation of ATG1 by PKA has no effect on ATG1 kinase activity. 111 The SNF1 kinase, a key factor in glucose sensing, has also been implicated in autophagy, since deletion of this gene completely blocked autophagy induced by nitrogen starvation. 112 Finally, the GCN2 kinase, which responds to amino acid availability, appears to regulate autophagy via the GCN4 transcription factor. 109,113 A role for TOR has also been proposed in microautophagy, a catabolic process where portions of cytosol or whole organelles are sequestered directly at the surface of the vacuole/lysosome by protrusion, septation and/or invagination of the limiting membrane. 114 Microautophagy primarily serves to counterbalance the massive influx of membranous material towards the vacuolar/lysosomal membrane that occurs during continuous fusion of the outer membrane of autophagosomes. Studies performed in yeast indicate an essential role of the EGO complex, which localizes at the vacuolar membrane, in activation of microautophagy following rapamycininduced, autophagy-mediated membrane influx toward the vacuolar membrane. 78 It has been suggested that microautophagy reestablishes a balance in the distribution of membranes in the entire endomembranous system. 78 This general remodelling process may function to communicate the status of the internal vacuolar nutrient pool to TORC1, which localizes at multiple membranes including the vacuolar membrane. This attractive model is in agreement with the proposed role of EGO complex as an activator of TORC1 signaling (see above) Autophagy 855

6 Table 1 Genes involved in TOR signaling and autophagy in yeasts, humans, plants and algae S. cerevisiae H. sapiens A. thaliana C. reinhardtii TORC genes TOR1, TOR2 mtor AtTOR ref. 5 CrTOR 4 KOG1 raptor AtRaptor1A, AtRaptor1B 127,128 Single gene (XP_ ) d LST8 mlst8 Two genes (At3g18140, At2g22040) c CrLST8 129 TCO AVO1 hsin1 - - AVO AVO3 rictor - - BIT ATG genes a ATG1 Two genes b (ULK1, ULK2) Three genes Single gene (XM_ ) d ATG2 Two genes Single gene ATG3 Single gene Single gene 159 Single gene (XP_ ) d ATG4 Gene family Two genes 147 Single gene (XP_ ) d ATG5 Single gene Single gene 150 Single gene (XP_ ) d ATG6 Single gene (BECLIN 1) Single gene 136,159 Single gene (XP_ ) d ATG7 Single gene Single gene 146 Single gene (XP_ ) d ATG8 Gene family (LC3, GATE-16, GABARAP) Gene family 147 Single gene (XP_ ) d ATG9 Two genes Single gene ATG10 Single gene Single gene 141 Two genes (XP_ , XP_ ) d ATG ATG12 Single gene Two genes 142,143 Single gene (XP_ ) d ATG13 Single gene Two genes - ATG ATG ATG16 Two genes Single gene - ATG ATG18 Two genes Gene family 151 Single gene (XP_ ) d ATG ATG20 - Gene family Single gene (10196) e ATG ATG22 - Single gene - ATG Single gene (175224) e ATG24 Two genes - - a Predicted number of homologs to yeast ATG genes in humans, plants and algae. b Homologues in plants and human are partially based on Meijer et al., 115 and Bassham et al. 135 c TIGR locus name. d NCBI gene database. e JGI protein ID number at the C. reinhardtii v3.0 genome database. -, no homolog found. In metazoans, withdrawal of nutrients or inhibition of TORC1 signaling also elicits autophagy. Homologs of ATG1 have been shown to be involved in autophagy in multicellular organisms, although the precise role of the ATG1 complex during the formation of the autophagosome remains elusive. Several components of the ATG1 complex such as ATG11, ATG13 or ATG17 do not seem to be evolutionarily conserved, 115 and no physiological targets of ATG1 have been identified so far. A recent study in Drosophila demonstrates that the kinase activity of ATG1 seems to be required to stimulate autophagy, 116 in agreement with previous findings in yeast. 100,101 Interestingly, this study also shows that ATG1 negatively feeds back on TOR signaling (Fig. 1). Overexpression of ATG1 results in a downregulation of TOR activity, leading to a further activation of autophagy and reduced cell growth. 116 Accordingly, it has been demonstrated that overexpression of ATG1 in Drosophila and mammalian cells interferes with TOR signaling by inhibiting S6K activity, 117 indicating that a crosstalk exists between autophagy and cell growth regulation. 116,117 The mtorc1 target S6K was initially proposed to suppress autophagy. 118 However, this model was refuted by the finding that S6K is essential for autophagy in the fat body of Drosophila. 119 In mammalian cells, S6K has been proposed to contribute to the basal activity of autophagy via its feedback inhibition of the PI3K-dependent insulin signaling pathway 120 (see above; Fig. 1). Therefore, S6K appears to regulate autophagy both directly and indirectly via feedback regulation of PI3K/Akt/TOR signaling. However, the precise role of S6K in autophagy requires further investigation. 856 Autophagy 2008; Vol. 4 Issue 7

7 Figure 2. Regulation of autophagy by the TOR pathway in yeast. The activity of the ATG1 kinase regulates the switch from the Cvt pathway to autophagy. ATG1 activity is modulated by its association to different regulatory proteins under different nutrient conditions. The nutritional status of the cell might be signalled to TORC1 either directly or through the EGO complex (EGOC). In the presence of nutrients, TORC1 promotes (directly or indirectly) phosphorylation of ATG13, a regulatory subunit of ATG1. In its hyperphosphorylation state, ATG13 has low affinity for ATG1 and autophagy is inhibited. Ras/PKA signaling may also contribute to inhibit autophagy by maintaining ATG1 phosphorylated. Rapamycin treatment or nutrient starvation results in the rapid dephosphorylation of ATG13, which increases the affinity of this protein for ATG1 and activates autophagy. TORC1 also controls autophagy via regulation of the transcription factor GLN3. Dashed lines refer to potential interactions. TOR Signaling in Photosynthetic Eukaryotes Control of cell growth by TOR is conserved among eukaryotes, and many aspects of the TOR signaling pathway are similar in evolutionary distant organisms such as animals and fungi. However, important differences have also been found in the TOR cascade in metazoans, likely due to physiological adaptations of these organisms. In addition to mammalian, insect and yeast cells, TOR proteins have been described in photosynthetic eukaryotes including the model plant Arabidopsis thaliana and the model unicellular green alga Chlamydomonas reinhardtii. 4,5 The Arabidopsis genome contains a single TOR gene (AtTOR) which encodes a protein with high identity to mammalian or yeast TORs. Similarly, investigation of the Chlamydomonas genome reveals that TOR is also conserved in green algae and a single TOR gene (CrTOR) can be identified in this unicellular organism. The analyses of AtTOR and CrTOR revealed that both proteins contain domains highly conserved in TOR kinases, including the FKBP-rapamycin-binding (FRB) domain, the C-terminal kinase domain, N-terminal HEAT repeats, and the FAT and FATC domains characteristic of phosphatidylinositol 3-kinase related kinases. 4,5 TOR has been involved in control of cell growth in both plants and algae. Similar to the TOR proteins from nonphotosynthetic eukaryotes, AtTOR is essential for plant cell growth. 5,121 The analysis of T-DNA insertion mutants in the AtTOR gene revealed that disruption of AtTOR leads to the premature arrest of endosperm and embryo development. 5,121 Along their life cycle, plant cells may experience different modes of growth. 122 The meristems are specialized structures where new cells are continually formed and generate all the organs in the plant. Growth of meristematic cells is coupled to cell division and is characterized by an important level of protein synthesis. Once plant cells progressively exit from the meristematic zones during the formation of organs, they can reach a large size by a process of cell expansion, which is driven by water accumulation into a large vacuole and by cell wall production. The phenotypic analysis of tor null mutant embryos strongly suggests that AtTOR is not required for the process of cell expansion but rather plays a key role in the control of overall cell mass increase during cell growth. 5 Thus, AtTOR appears to be necessary only for cytosolic growth but not cell division itself. Unlike yeasts, mammals or flies, the vegetative growth of Arabidopsis and other plants such as rice or tobacco is not sensitive to rapamycin. 5 This natural resistance of plants to rapamycin has hampered investigations of the plant TOR kinase. Given that the resistance of plants to rapamycin is not the consequence of the absence of a TOR pathway, a feasible explanation for this behaviour of land plants might be the inability of plant FKBP12 to bind rapamycin. Although FKBP12 is highly conserved in plants, it has been reported that plant FKBP12 has evolved structural changes that hamper this protein to mediate the action of its drug ligands against the functional targets. 123 In contrast to Arabidopsis, Chlamydomonas is sensitive to rapamycin. Treatment of Chlamydomonas cells with rapamycin caused strong inhibition of cell growth, suggesting that a growth-controlling pathway that must include TOR and FKBP12 homologs is conserved in this unicellular organism. 4 The Chlamydomonas nuclear genome contains a single FKBP12 gene (CrFKBP12) that is more distant to plant than human or yeast homologs. Drug sensitivity assays in a yeast FKBP12 mutant demonstrated that unlike plant FKBP12, CrFKBP12 is able to bind rapamycin in vivo although less efficiently than yeast or mammalian homologs. 4 A detailed study of the region in FKBP12 involved in rapamycin binding showed that all residues that establish hydrogen bonds with rapamycin are conserved in CrFKBP12 with the exception of a glutamine residue at position 53 (with respect to human FKBP12). Addition of a Gln residue at this position in CrFKBP12 Autophagy 857

8 increased the capacity of this protein for rapamycin binding to the same level than its yeast homologue. 4 These data support the hypothesis that resistance of plants to rapamycin might be a consequence of evolution of plant FKBP12 into a protein unable to bind rapamycin, since substitution of certain residues in the amino acid sequence of a FKBP12 protein may lead to significant changes in rapamycin binding. Moreover, the hypothesis that sensitivity of Chlamydomonas to rapamycin is due to the capacity of CrFKBP12 to bind this drug was genetically confirmed by the identification of a spontaneous Chlamydomonas mutant lacking the FKBP12 protein which exhibited fully resistance to rapamycin. 4 Despite differences in rapamycin sensitivity, plant and alga TORs are still able to bind to the FKBP12-rapamycin complex. Pull-down experiments demonstrated that the FRB domain of CrTOR interacts with CrFKBP12 in the presence of rapamycin. 4 Recently, it has been shown that none of the FKBPs, including FKBP12, from Arabidopsis is able to form a ternary complex with the FRB domain of AtTOR in the presence of rapamycin. 5,124 However, genetic and biochemical studies showed that the FRB domain of AtTOR is still able to interact, in a rapamycin-sensitive manner, with yeast or mammalian FKBP12, indicating that the FRB domain of TOR is functionally conserved among all eukaryotes regardless of the presence of FKBP proteins. 5,121 These findings also suggest that rapamycin susceptibility in plants might be restored by the expression of a heterologous FKBP12 protein. Such a transgenic line expressing yeast FKBP12 has recently been generated in Arabidopsis. 124 Interestingly, the analysis of this transgenic plant showed that rapamycin only caused reduction of the primary root growth and a lowered accumulation of high molecular weight polysomes. Since AtTOR is essential for plant cell growth, these findings suggest that rapamycin is partially inhibiting TOR function(s) in this rapamycin-sensitive line. Two hypotheses may explain this low effect of rapamycin on TOR activity in this transgenic line. Rapamycin-sensitive functions of TOR in plants might be significantly reduced compared to other eukaryotes naturally sensitive to this drug like yeast. According to this model, a subset of TOR functions that are putatively controlled by TORC1 may have become resistant to the action of rapamycin due to specialized evolution of the plant TOR pathway. Alternatively, it is also possible that the rapamycin-fkbp12 complex does not efficiently bind to the FRB domain of AtTOR in vivo. Thus, extensive work remains to be done in order to explore these two hypotheses. In plants, expression of the AtTOR gene is limited to zones where cell proliferation is coupled to cytosolic growth, such as primary apical and root meristems, embryo and endosperm, and no significant expression is observed in differentiated cells. 5 This expression pattern is in contrast to TOR expression in mammalian cells, where mtor is present in all tissues. A positive correlation between plant growth and the level of AtTOR expression has been recently demonstrated in Arabidopsis. Downregulation of AtTOR expression by inducible RNAi results in a dose-dependent decrease in organ and cell size as well as a post-germinative halt in growth and development, while overexpression of AtTOR leads to an overall increase in cell and organ size. 125 Taken together, these findings demonstrate that TOR also acts as a master regulator of cell growth in photosynthetic eukaryotes (Fig. 3). TOR complexes in plants and algae. Components of TORC1 are conserved in photosynthetic eukaryotes (Table 1). Two genes are coding for KOG1/raptor homologs in the Arabidopsis Figure 3. The TOR pathway in photosynthetic eukaryotes. Homologues to the TORC1 components KOG1/raptor and LST8 have been identified in Arabidopsis and Chlamydomonas, respectively. TORC1 might control cell growth by regulating embryo development, translation via S6K and EBP1 homologues, and autophagy in response to nutrients and/or osmotic stress. In addition to TORC1 signaling, plant S6K is regulated by PDK1 in response to an unknown signal. See text for further details. genome, 121, while a single raptor-like gene is present in the nuclear genome of Chlamydomonas ( org/chlre3/chlre3.home.html) and the red alga Cyanidioschyzon merolae (Locus CMH109C, The AtRaptor1 (At3g08850) and AtRaptor2 (At5g01770) proteins from Arabidopsis are 76% identical and, similar to other raptor homologues, contain HEAT repeats, WD40 motifs and the raptor N-terminal conserved/caspase (RNC/C) motif. 121,127,128 AtRaptor1 and AtRaptor2 show similar expression patterns and both transcripts accumulate in all developmental stages. 127,128 However, the expression level of AtRaptor1 is higher than the one of AtRaptor2, which might be an indicative of a different functionality of these two genes. 127,128 Accordingly, disruption of the AtRaptor2 gene does not lead to any visible phenotype while mutations in AtRaptor1 cause negative effects on plant growth and development. 127,128 Whether AtRaptor1 is, like AtTOR, an essential gene is controversial, since it has been reported that mutant homozygous for AtRaptor1 disruptions are either lethal 128 or severely affected in development, 127 leading to the conclusion that AtTOR activity in embryonic development does not require AtRaptor. KOG1/raptor is essential for cell growth in yeast and mammals 7,29 and given the high conservation of TOR and KOG1/raptor functions through evolution, it would be predictable that the activity of AtRaptor is also essential for embryonic development in plants. Direct interaction of AtRaptor1 with the HEAT repeats of AtTOR has been demonstrated, 121 indicating that at least TORC1 might be conserved in plants. As elaborated below, binding of AtRaptor1 to AtTOR may be important for TOR activity since AtRaptor1 is also able to interact in vivo with AtTOR substrates. Besides KOG1/raptor and a TOR protein kinase, TORC1 also includes the conserved LST8 protein. LST8 homologs have been identified in photosynthetic eukaryotes. The Arabidopsis nuclear 858 Autophagy 2008; Vol. 4 Issue 7

9 genome contains two putative homologues of yeast and mammalian LST8, AtLST8.1 (At3g18140) and AtLST8.2 (At2g22040) ( while a single LST8 gene, OsLST8 (Os03g47780) can be identified in the rice genome ( org). Chlamydomonas contains a functional LST8 gene, CrLST8, whose product has high homology to the LST8 protein from other eukaryotes. 129 CrLST8 forms part of a rapamycin-sensitive TOR complex in Chlamydomonas, as it can be co-purified with CrTOR and CrFKBP12 in the presence of rapamycin. 129 Yeast and mammalian LST8s bind to the kinase domain of TOR proteins, and this interaction is required for full catalytic activity of TOR. 23,28 CrLST8 is able to bind to purified kinase domain of CrTOR, suggesting that CrLST8 may perform a similar function in Chlamydomonas. 129 Yeast complementation assays have demonstrated that CrLST8 is able to functionally and structurally replace endogenous yeast LST8, indicating that LST8 functions must be conserved in photosynthetic organisms. 129 Moreover, using yeast cells as a heterologous system for CrLST8 expression, it has been demonstrated that mutations at certain positions of CrLST8 resulted in a complete inactivation of the protein and a failure to interact with yeast TOR2. The functional analysis of these CrLST8 null mutants in yeast allowed to directly link cell growth to the interaction of CrLST8 with TOR. 129 No obvious homologues exist for the TORC2-specific proteins AVO1/hSIN1 and AVO3/rictor in plants and algae, raising the question of whether TORC2 is structurally conserved in photosynthetic organisms. It is possible, however, that similar to other eukaryotes, plants and algae functionally maintain a TORC2 complex, although the proteins that constitute this putative complex may substantially differ from their yeast and mammalian counterparts. As mentioned above, mammalian and yeast TORCs are primarily membrane associated. Cellular localization of TOR and LST8 proteins in photosynthetic organisms has been addressed in Chlamydomonas. Biochemical fractionation and indirect immunofluorescence microscopy studies indicated that CrTOR and CrLST8 exist in high-molecular-mass complexes that tightly associate with membranes from the endoplasmic reticulum (ER) system, and are particularly abundant close the basal body, 129 a membrane-enriched region where flagella anchor to the cell. The functional significance of CrTOR and CrLST8 association to ER membranes remains to be determined. TOR functions in photosynthetic organisms. TOR has been implicated in the control of important cellular processes, all of them required for the regulation of cell growth in eukaryotes. Most of these functions have been assigned to TOR by utilizing rapamycin as a specific inhibitor of TOR activity. Therefore, the impossibility of using rapamycin to specifically block TOR activity in plants has hindered the identification of TOR readouts in these organisms. Nevertheless, the analysis of transgenic plants with reduced or increased AtTOR as well as the study of the AtTOR partner AtRaptor1 has led to the initial dissection of the plant TOR pathway. Disruption of the AtTOR gene leads to embryonic arrest, 5 indicating that TOR activity is involved in embryo development in Arabidopsis. The developmental arrest of a tor mutant embryo at the globular stage correlates with the change from divisions without growth to divisions coupled with growth. Therefore AtTOR is probably required for premitotic cytoplasmic growth during cell differentiation. 5 Control of embryo development by AtTOR is likely to require AtRaptor1 since mutation of this gene has been reported to arrest embryo development. 128 In addition to embryo development regulation, it has been proposed that AtRaptor1 may have other activities in plants. Binding of AtRaptor1 to a Mei2-like protein by yeast two-hybrid has been reported. 126 Mei2 is a RNA-binding protein that participates in meiosis in yeast, 130 and interestingly, this protein has been reported to interact with Mip1, the raptor homologue in fission yeast. 131 Whether the raptor-mei2 interaction constitutes a conserved branch of the fission yeast and plant TOR pathways awaits further investigation. Regulation of AGC kinases by TOR is conserved in yeast and mammalian cells. 132 Two AGC kinases, mammalian S6K and yeast SCH9, are direct targets of TORC1. The Arabidopsis genome contains two putative S6K homologues, S6K1 and S6K2, 133 and at least S6K1 appears to function as a direct target of AtTOR in plants. AtRaptor1 interacts with the HEAT repeats of AtTOR as well as S6K1 in vivo. 121 Moreover, it has been demonstrated that AtRaptor1 regulates the kinase activity of S6K1 over the ribosomal protein S Therefore, similar to the mammalian system, AtTOR may control cell growth by S6K1-mediated phosphorylation of S6. The kinase activity of S6K1 is affected by osmotic stress, suggesting that AtTOR is involved in the regulation of the metabolic adjustment of plant cells to osmotic stress 121 (Fig. 3). Experiments designed to monitor S6K1 activity in cells overexpressing AtRaptor1 and/or AtTOR HEAT repeats under osmotic stress conditions suggest that osmotic stress affects S6K1 activity downstream of AtTOR instead of by the direct inhibition of AtTOR kinase activity. 121 The hypothesis that TOR signaling and osmotic stress are intimately linked in plants is also supported by the finding that AtTOR expression is correlated with sensitivity to osmotic stress. Transgenic plants that overexpress AtTOR exhibit tolerance to osmotic stress, whereas a decrease in AtTOR expression results in hypersensitivity to this stress. 125 Given that TOR controls cell growth by regulating mrna translation among other readouts, it would be interesting to investigate whether the sensitivity to osmotic stress of plants with reduced AtTOR function is due to a negative effect on translation. Inactivation of the TOR pathway in yeast by rapamycin treatment or nutrient limitation results in a pronounced reduction of high molecular weight polysomes, 55 which correspond to actively transcribed mrna. Similarly, silencing of AtTOR decreases accumulation of polysomes, 125 although to a minor extent compared with the reduction observed in yeast cells that have been treated with rapamycin. These findings indicate that TOR might be also involved in the control of mrna translation in plants. Interestingly, expression of a putative Arabidopsis homologue to human EBP1, which regulates ribosome assembly and translation, 134 has been correlated with variations in AtTOR expression, suggesting that AtEBP1 might act downstream of the TOR kinase on the mrna translation machinery in plants. 125 Control of protein synthesis by the TORC1 pathway was identified in yeast and mammalian cells by using rapamycin as a specific inhibitor of TOR kinases. As discussed in this section, protein translation has been proposed to be under the control of TOR in plants, although the natural resistance of these organisms to rapamycin hampers the molecular dissection of this TOR pathway. Therefore, the generation of rapamycin-sensitive plants through expression of a FKBP12 protein able to bind rapamycin similar to the one recently Autophagy 859

Cell Biology Review. The key components of cells that concern us are as follows: 1. Nucleus

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