Coordinating cell growth with nutrient availability is critical for cell survival. The evolutionarily conserved TOR (target of rapamycin) controls cell growth in response to nutrients, in particular amino acids. As a central controller of cell growth, mTOR (mammalian TOR) is implicated in several disorders, including cancer, obesity, and diabetes. Here, we review how nutrient availability is sensed and transduced to TOR in budding yeast and mammals. A better understanding of how nutrient availability is transduced to TOR may allow novel strategies in the treatment for mTOR-related diseases.

This is an unusual plant-specific b subunit that contains the C-terminal domain but lacks a CBM (carbohydrate-binding module).b By sequence, this appears to be an ortholog of mammalian g subunits, but it does not appear to form functional heterotrimers (Zhao, 2019).This is an unusual plant-specific g subunit that contains a CBM (carbohydrate-binding module) fused to the four CBS motifs found in other AMPK-g subunits.dThis is probably a non-functional protein (Moreau et al., 2012).

Type 2C protein phosphatases are encoded in Saccharomyces cerevisiae by several related genes (PTC1-5 and PTC7). To gain insight into the functions attributable to specific members of this gene family, we have investigated the transcriptional profiles of ptc1-5 mutants. Two main patterns were obtained as follows: the one generated by the ptc1 mutation and the one resulting from the lack of Ptc2-5. ptc4 and ptc5 profiles were quite similar, whereas that of ptc2 was less related to this group. Mutation of PTC1 resulted in increased expression of numerous genes that are also induced by cell wall damage, such as YKL161c, SED1, or CRH1, as well as in higher amounts of active Slt2 mitogen-activated protein kinase, indicating that lack of the phosphatase activates the cell wall integrity pathway. ptc1 cells were even more sensitive than slt2 mutants to a number of cell wall-damaging agents, and both mutations had additive effects. The sensitivity of ptc1 cells was not dependent on Hog1. Besides these phenotypes, we observed that calcineurin was hyperactivated in ptc1 cells, which were also highly sensitive to calcium ions, heavy metals, and alkaline pH, and exhibited a random haploid budding pattern. Remarkably, many of these traits are found in certain mutants with impaired vacuolar function. As ptc1 cells also display fragmented vacuoles, we hypothesized that lack of Ptc1 would primarily cause vacuolar malfunction, from which other phenotypes would derive. In agreement with this scenario, overexpression of VPS73, a gene of unknown function involved in vacuolar protein sorting, largely rescues not only vacuolar fragmentation but also sensitivity to cell wall damage, high calcium, alkaline pH, as well as other ptc1-specific phenotypes.

No abstract

Unlike most other organisms, the essential five-step Coenzyme A biosynthetic pathway has not been fully resolved in yeast. Specifically, the gene(s) encoding the phosphopantothenoylcysteine decarboxylase (PPCDC) activity still remains unidentified.Sequence homology analyses suggest three candidates, namely Ykl088w, Hal3 and Vhs3, as putative PPCDC enzymes in Saccharomyces cerevisiae. Interestingly, Hal3 and Vhs3 have been characterized as negative regulatory subunits of the Ppz1 protein phosphatase. Here we show that YKL088w does not encode a third Ppz1 regulatory subunit, and that the essential roles of Ykl088w and the Hal3/Vhs3 pair are complementary, cannot be interchanged and can be attributed to PPCDC-related functions. We demonstrate that while known eukaryotic PPCDCs are homotrimers, the active yeast enzyme is a heterotrimer which consists of Ykl088w and Hal3/Vhs3 monomers that separately provides two essential catalytic residues.Our results unveil Hal3/Vhs3 as moonlighting proteins, involved in both CoA biosynthesis and protein phosphatase regulation. 3Coenzyme A (CoA, 1) is a ubiquitous and essential cofactor that is utilized by a wide variety of enzymes in reactions where it mainly acts as a carrier and activator of acyl groups 1, 2 . The CoA biosynthetic pathway has been elucidated in various diverse species, including eubacteria (Escherichia coli), plants (Arabidopsis thaliana), and mammals (Homo sapiens) 1,3,4 . These studies have shown that the pathway is universal and consists of the same five enzymatic transformations in all cases, although some diversity exist among the specific proteins that catalyze certain steps 5 . Nonetheless, bioinformatic approaches allow identifying (with a few exceptions 6 ) candidate genes encoding the CoA biosynthetic proteins in nearly all organisms, including Saccharomyces cerevisiae.Interestingly, sequence homology searches suggest three proteins, namely Hal3, Vhs3 and Ykl088w, as candidates that may exhibit phosphopantothenoylcysteine decarboxylase (PPCDC) activity in S. cerevisiae. PPCDC is a flavoprotein that catalyzes the decarboxylation of 4'-phosphopantothenoylcysteine (PPC; 2) to yield 4'-phosphopantetheine (PP; 3), the third step in CoA biosynthesis. While previous studies on PPCDCs have shown some diversity among these enzymes (e.g. the bacterial variants are usually bifunctional proteins that also have phosphopantothenoylcysteine synthetase (PPCS) activity), they all share a common mechanism and active site architecture [7][8][9][10][11] . Furthermore, all PPCDCs characterized so far are monogenic. While the three PPCDC candidates in S. cerevisiae are indeed very similar (Vhs3 and Ykl088w have 49% and 28% sequence identity to the Hal3 protein respectively, see Figure 1a), the identification of Hal3 and Vhs3 as potential PPCDCs is in fact surprising as both proteins have previously been shown to have functions completely unrelated to CoA biosynthesis.Specifically, Hal3 (also known as Sis2) is a conserved protein originally identified as a halotoler...