The decision by a cell to enter a round of growth and division must be intimately coordinated with nutrient availability and its metabolic state. These metabolic and nutritional requirements, and the ...mechanisms by which they induce cell growth and proliferation, remain poorly understood. Herein, we report that acetyl-CoA is the downstream metabolite of carbon sources that represents a critical metabolic signal for growth and proliferation. Upon entry into growth, intracellular acetyl-CoA levels increase substantially and consequently induce the Gcn5p/SAGA-catalyzed acetylation of histones at genes important for growth, thereby enabling their rapid transcription and commitment to growth. Thus, acetyl-CoA functions as a carbon-source rheostat that signals the initiation of the cellular growth program by promoting the acetylation of histones specifically at growth genes.
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► A burst of acetyl-CoA production accompanies and triggers entry into growth ► SAGA dynamically acetylates its substrates in tune with acetyl-CoA levels ► SAGA is recruited to activate growth genes during growth ► Acetylated histones are highly enriched at growth genes, specifically during growth
Autophagy is a process of cellular self-digestion induced by various forms of starvation. Although nitrogen deficit is a common trigger, some yeast cells induce autophagy upon switch from a rich to ...minimal media without nitrogen starvation. We show that the amino acid methionine is sufficient to inhibit such non-nitrogen-starvation (NNS)-induced autophagy. Methionine boosts synthesis of the methyl donor, S-adenosylmethionine (SAM). SAM inhibits autophagy and promotes growth through the action of the methyltransferase Ppm1p, which modifies the catalytic subunit of PP2A in tune with SAM levels. Methylated PP2A promotes dephosphorylation of Npr2p, a component of a conserved complex that regulates NNS autophagy and other growth-related processes. Thus, methionine and SAM levels represent a critical gauge of amino acid availability that is sensed via the methylation of PP2A to reciprocally regulate cell growth and autophagy.
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•Iml1/Npr2/Npr3 complex regulates autophagy induced in response to limited methionine•Methionine inhibits autophagy and promotes growth through the methylation of PP2A•Methylation of PP2A is responsive to SAM levels and regulates phosphorylation of Npr2•Methionine may impact the phosphostatus of proteins and TORC1 substrates via PP2A
Yeast cells sense and respond to levels of cellular methionine through regulation of PP2A to control choices between autophagy and cell growth upstream of mTORC1.
Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key ...indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a ‘growth’ or ‘fed’ state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under ‘survival’ or ‘fasted’ states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitate the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes.
Pbp1 (poly(A)-binding protein-binding protein 1) is a cytoplasmic stress granule marker that is capable of forming condensates that function in the negative regulation of TORC1 signaling under ...respiratory conditions. Polyglutamine expansions in its mammalian ortholog ataxin-2 lead to spinocerebellar dysfunction due to toxic protein aggregation. Here, we show that loss of Pbp1 in S. cerevisiae leads to decreased amounts of mRNAs and mitochondrial proteins which are targets of Puf3, a member of the PUF (Pumilio and FBF) family of RNA-binding proteins. We found that Pbp1 supports the translation of Puf3-target mRNAs in respiratory conditions, such as those involved in the assembly of cytochrome c oxidase and subunits of mitochondrial ribosomes. We further show that Pbp1 and Puf3 interact through their respective low complexity domains, which is required for Puf3-target mRNA translation. Our findings reveal a key role for Pbp1-containing assemblies in enabling the translation of mRNAs critical for mitochondrial biogenesis and respiration. They may further explain prior associations of Pbp1/ataxin-2 with RNA, stress granule biology, mitochondrial function, and neuronal health.
S-adenosylmethionine (SAM) is the methyl donor for biological methylation modifications that regulate protein and nucleic acid functions. Here, we show that methylation of a phospholipid, ...phosphatidylethanolamine (PE), is a major consumer of SAM. The induction of phospholipid biosynthetic genes is accompanied by induction of the enzyme that hydrolyzes S-adenosylhomocysteine (SAH), a product and inhibitor of methyltransferases. Beyond its function for the synthesis of phosphatidylcholine (PC), the methylation of PE facilitates the turnover of SAM for the synthesis of cysteine and glutathione through transsulfuration. Strikingly, cells that lack PE methylation accumulate SAM, which leads to hypermethylation of histones and the major phosphatase PP2A, dependency on cysteine, and sensitivity to oxidative stress. Without PE methylation, particular sites on histones then become methyl sinks to enable the conversion of SAM to SAH. These findings reveal an unforeseen metabolic function for phospholipid and histone methylation intrinsic to the life of a cell.
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•Phospholipid methylation is the major consumer of SAM•Phospholipid methylation enables conversion of SAM to other sulfur metabolites•Lack of phospholipid methylation causes hypermethylation of histones and PP2A•Histones are methyl sinks in the absence of phospholipid methylation
Ye et al. show that methylation of phosphatidylethanolamine for the synthesis of phosphatidylcholine is the major consumer of SAM and is required for the efficient synthesis of cysteine and glutathione. Cells lacking phospholipid methylation accumulate SAM and exhibit hypermethylation of histones, revealing a role for phospholipids and histones as methyl group sinks, which is required for optimal cellular metabolism, signaling, and transcriptional regulation.
Protein translation is an energetically demanding process that must be regulated in response to changes in nutrient availability. Herein, we report that intracellular methionine and cysteine ...availability directly controls the thiolation status of wobble-uridine (U34) nucleotides present on lysine, glutamine, or glutamate tRNAs to regulate cellular translational capacity and metabolic homeostasis. tRNA thiolation is important for growth under nutritionally challenging environments and required for efficient translation of genes enriched in lysine, glutamine, and glutamate codons, which are enriched in proteins important for translation and growth-specific processes. tRNA thiolation is downregulated during sulfur starvation in order to decrease sulfur consumption and growth, and its absence leads to a compensatory increase in enzymes involved in methionine, cysteine, and lysine biosynthesis. Thus, tRNA thiolation enables cells to modulate translational capacity according to the availability of sulfur amino acids, establishing a functional significance for this conserved tRNA nucleotide modification in cell growth control.
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•tRNA thiolation is actively downregulated when sulfur amino acids are limiting•Sulfur amino acids modulate translational capacity using thiolated tRNAs•tRNA thiolation is important for amino acid homeostasis
Reductions in cellular cysteine and methionine levels trigger amino acid synthesis and salvage pathways and a reduction in protein synthesis via inhibition of tRNA uridine thiolation.
Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that ...integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player in bacterial stress response and persistence. We reveal that (p)ppGpp activates global metabolic changes upon starvation, allowing survival by regulating GTP. Combining metabolomics with biochemical demonstrations, we find that (p)ppGpp directly inhibits the activities of multiple GTP biosynthesis enzymes. This inhibition results in robust and rapid GTP regulation in Bacillus subtilis, which we demonstrate is essential to maintaining GTP levels within a range that supports viability even in the absence of starvation. Correspondingly, without (p)ppGpp, gross GTP dysregulation occurs, revealing a vital housekeeping function of (p)ppGpp; in fact, loss of (p)ppGpp results in death from rising GTP, a severe and previously unknown consequence of GTP dysfunction.
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► (p)ppGpp allows survival of amino acid starvation by reducing GTP levels ► (p)ppGpp directly and potently inhibits multiple GTP biosynthesis enzymes ► (p)ppGpp is a key component of GTP homeostasis ► In the absence of (p)ppGpp, high GTP levels lead to cell death
Epigenetic modifications on chromatin are most commonly thought to be involved in the transcriptional regulation of gene expression. Due to their dependency on small-molecule metabolites, these ...modifications can relay information about cellular metabolic state to the genome for the activation or repression of particular sets of genes. In this review we discuss emerging evidence that these modifications might also have a metabolic purpose. Due to their abundance, the histones have the capacity to store substantial amounts of useful metabolites or to enable important metabolic transformations. Such metabolic functions for histones could help to explain the widespread occurrence of particular modifications that may not always be strongly correlated with transcriptional activity.
Histone methylation and acetylation are sensitive to metabolic states.
Histone methylation consumes SAM, enabling histones to function as a methyl sink.
Histone acetylation deposits acetyl units as a source of acetate.
‘Bulk’ histone methylation and acetylation might reflect these metabolic functions.
Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of ...metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure ) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites.
Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using 13C-NMR analysis of brain tumors resected from patients during infusion of ...13C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize 1,2-13Cacetate and can do so while simultaneously oxidizing 1,6-13Cglucose. The tumors do not oxidize U-13Cglutamine. In vivo oxidation of 1,2-13Cacetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.
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•13C-acetate can be oxidized by glioblastoma human orthotopic models in vivo•A wide range of brain metastasis orthotopic models can oxidize 13C-acetate in vivo•13C-acetate infused in patients is oxidized by glioblastoma and brain metastases•Acetyl-CoA synthetase 2 is highly expressed in human brain tumors
Oxidation of acetate into the Krebs cycle occurs in primary and metastatic tumors in vivo, indicating acetate as a widespread bioenergetic substrate for cancer progression.
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