TOR Complexes in Yeast
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TOR Complexes in Yeast
TOR (Target of Rapamycin) is a PIKK (Phosphatidylinositol Kinase-related protein Kinase) that controls cell growth and proliferation. In all eukaryotic cells expressing the protein, TOR function is controlled by nutrient availability, which ensures that protein synthesis is repressed when the supply of precursor amino acids is insufficient. In mammalian cells, one branch of this pathway controls general translational initiation, whereas a separate branch specifically regulates the translation of r-protein (ribosomal protein) mRNAs. In simple organisms, nutrient availability appears to be the major factor influencing TOR activity. In budding yeast, Saccharomyces cerevisiae the TOR pathway similarly regulates general translational initiation, but its specific role in the synthesis of ribosomal components is not well understood. In addition to general effects on translational initiation, TOR exerts drastic control over r-protein gene transcription as well as the synthesis and subsequent processing of 35S precursor rRNA. TOR signaling is a prerequisite for the induction of r-protein gene transcription that occurs in response to improved nutrient conditions. TOR cascade plays a prominent role in regulating transcription in response to nutrients in addition to its known roles in regulating translation, ribosome biogenesis, and amino acid permease stability (Ref.1).

In budding yeast, there are two TOR complexes TOR1 and TOR2 that controls many growth-related processes in response to nutrients and favorable environmental conditions. TORC1 (TOR Complex-1) contains TOR1 or TOR2, Kog1 (YHR186c), and Lst8. TORC2 (TOR Complex-2) contains TOR2, Avo1 (YOL078w), Avo2 (YMR068w), Avo3 (YER093c), and Lst8. These distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. The yeast TORs control many of the above processes via a protein phosphatase switch composed of PP2As (Type 2A-related phosphatase), SIT4 (Supressors of Initiation of Transcription-4), Tap42 (Type 2A-Phosphatase Associated protein, 42kDa), and Tap41 (TAP42-interacting protein, 41kDa) (Ref.2). Under good nutrient conditions, TOR promotes binding of SIT4 to TAP42 and thereby maintains SIT4 inactive. Under nutrient limitation or rapamycin treatment, SIT4 dissociates from its inhibitor Tap42 and TOR globally represses starvation-specific transcription by sequestering the kinase NPR1 (Nitrogen Permease Reactivator-1) and Tap41, and several nutrient-responsive transcription factors, such as the GATA factors Gln3 (Glutamine) and GAT1, the zinc finger transcription factors MSN2 (Multicopy Suppressors of Snf1 Mutation) and MSN4, and the bHLH (basic Helix-Loop-Helix)/Zip factor Rtg1/3 (Retrograde signaling protein), in the cytoplasm (Ref.3). Dephosphorylated Tap41, as part of a feedback loop, binds and inhibits Tap42, and thereby further amplifies SIT4 activity. TOR prevents the transcription of genes normally induced on nitrogen limitation by promoting the association of Gln3 with the cytoplasmic Ure2 protein. When cells are exposed to limiting nitrogen sources, intracellular Gln3 decreases, Ure2 is inactivated, and Gln1 (Glutamine synthetase) and Gln3 are activated, increasing Gln3 and inducing nitrogen utilization genes. Gln3 activates genes encoding Gln1, Glt1 (Glutamate synthase), GDh1 and GDh2 (Glutamate Dehydrogenase), permeases for nitrogenous compounds (GAP1 and Mep2), enzymes involved in nitrogen source metabolism (Dal3 and Put1), and transcription factors that regulate gene expression (Dal80 and Dal82) (Ref.1). Similarly, TOR and Tap42 maintain the protein kinase NPR1 in an inactive, phosphorylated state whereas TOR inactivation results in the SIT4-dependent dephosphorylation and activation of NPR1. The phosphorylation state of NPR1, in turn, impinges on the sorting and turnover of amino acid permeases such as the tryptophan permease TAT2 and possibly the general amino acid permease GAP1. Upon rapamycin treatment or nitrogen limitation, NPR1 is rapidly dephosphorylated and activated. Active NPR1 mediates the destabilization of TAT2 and the stabilization of GAP1. The activation of Gln3 and NPR1 upon nitrogen starvation leads to transcriptional and posttranscriptional induction of processes involved in scavenging secondary nitrogen sources (Ref.2). TOR also signals to the translation machinery via Tap42, but the mechanism by which Tap42 and/or the PP2A phosphatases are involved in the control of protein synthesis is unknown. TOR also negatively regulates Rtg1/3, MSN2, and MSN4 but does so independently of SIT4. The partially redundant transcription factors MSN2 and MSN4 activate a large number of stress-related genes in response to several types of stress, including carbon limitation. Rtg1 and Rtg3 and the cytoplasmic protein Rtg2 comprise an inter-organelle communication pathway termed retrograde regulation, which activates Rtg-target genes in the nucleus in response to a mitochondrial defect. Rtg2 is a negative regulator of Mks1 and Mks1 inhibits Rtg1-Rtg3. Rtg1 and Rtg3 form a heterodimer that activates expression of the genes encoding the TCA (Tricarboxylic Acid Cycle) and Glyoxylate Cycle enzymes, leading to the production of Alpha-ketoglutarate, a precursor of glutamate and ultimately glutamine. External glutamate or glutamine represses Rtg-dependent expression (Ref.4). Yeast TOR also controls rRNA and tRNA synthesis, via RNA PolI, PolII and PolIII, and processing of at least the 35S precursor rRNA. In the fission yeast Schizosaccharomyces pombe, rapamycin has no effect on vegetative growth, but blocks mating in response to nitrogen starvation.

In addition to its redundant function with TOR1 in a rapamycin-sensitive signaling pathway, TOR2 also has a rapamycin-insensitive function that TOR1 is unable to perform. TOR2-unique function mediates the cell cycle-dependent polarization of the actin cytoskeleton. A polarized actin cytoskeleton orients the secretory pathway toward a discrete growth site (the bud) and thereby determines the spatial growth pattern of yeast cells. TOR2 signals to the actin cytoskeleton by activating a Rho-type GTPase switch. More specifically, TOR2 activates the GEF (GDP/GTP Exchange Factor) Rom2 and Sac7. Rom2 in turn converts Rho1 to an active, GTP-bound state. GTP-bound Rho1 binds and activates PKC1 (Protein Kinase-C) (Ref.5). The PKC1 pathway maintains cell integrity by monitoring the cell wall state and senses cell wall damage and plasma membrane stress through Mid2 and the Wsc1/Slg1 family of cell surface sensors, which directly transmit the signal to Rom2 and Rho1. Among other targets, Rho1 directly up-regulate the glucan synthase machinery and also stimulate PKC1 activity allosterically. In turn, PKC1 activates a module of MAPK cascade. Thus, TOR, via the TOR-shared and TOR2-unique signaling pathways, appears to integrate the temporal and spatial control of cell growth.

The TOR pathway in yeast, senses a variety of nutrients to elicit a cellular response appropriate to a given nutrient condition and it may act as a multichannel processor to differentially regulate several physiological changes characteristic of starved cells, including inhibition of translation initiation, inhibition of ribosome biogenesis, specific changes in transcription, sorting and turnover of nutrient permeases, accumulation of storage carbohydrates (such as glycogen), G1 arrest, synthesis of storage carbohydrates, onset of autophagy, and entry into G0. Nitrogen (in particular glutamine) and possibly carbon are important nutrients in the context of yeast TOR signaling (Ref.6). Rapamycin can also stimulate sporulation of diploid yeast cells under appropriate conditions. Thus, in yeast, the TOR pathway couples protein synthesis to both cell growth and cell cycle progression in response to environmental cues.