Methionine Inhibits Autophagy and Promotes Growth by Inducing the SAM-Responsive Methylation of PP2A

Sutter, Benjamin M.; Wu, Xi; Laxman, Sunil; Tu, Benjamin P.

doi:10.1016/j.cell.2013.06.041

Cited by 216 publications

(279 citation statements)

References 51 publications

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“…Presently, little is known of the regulation of S-adenosyl methionine synthetase activity and the control of SAM uptake in the brain. In yeast, a mechanism for sensing SAM levels was revealed that would determine metabolic processes underlying growth (22). Possibly, the mammalian brain also has a mechanism for monitoring SAM levels that determines the neuronal response to environmental stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we investigated whether the inhibitory action of SAM on c-Fos and Egr-1 induction was due to an effect on H3S10p-K14ac formation. For instance, SAM has been shown to increase protein phosphatase activity via methylation (22). Treating rats with SAM before FS however did not affect the formation of H3S10p-K14ac in DG granule neurons (Fig.…”

Section: Sam Impairs Consolidation Of Fs-induced Behavioral Responsesmentioning

confidence: 99%

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Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5′-cytosine-phosphateguanine-3′) sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.stress | behavior | DNA methylation | immediate-early gene | hippocampus A daptation to stressful challenges is crucial for maintaining health and well-being. These events induce physiological and behavioral responses that enable the individual to cope with the challenge. In the brain, molecular mechanisms are initiated that facilitate learning of adaptive behavioral responses and the consolidation of memories of the event. Inappropriate responses to stress have been linked with psychiatric disorders, such as major depression and anxiety (1-3).Glucocorticoid hormones, secreted in response to a stressful challenge, in conjunction with activated intracellular signaling pathways in neurons of the hippocampus, play a key role in consolidating behavioral responses to stress (4, 5). The hippocampal extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathway, activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors, is involved in behavioral responses seen in Mo...

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Section: Discussionmentioning

confidence: 99%

Section: Sam Impairs Consolidation Of Fs-induced Behavioral Responsesmentioning

confidence: 99%

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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“…Methionine and S-adenosylmethionine (SAM) are essential metabolites that have gained considerable scientific attention because of their recently discovered roles as sentinel metabolites in the control of the eukaryotic cell cycle (10), autophagy (11), and differentiation of human pluripotent stem cells (12). Methionine takes a leading role in translation initiation (13) and is the precursor of SAM, a cofactor for one-carbon metabolism, the process responsible for the methylation of DNA, RNA, proteins, and lipids by SAM-dependent methyltransferases (14).…”

mentioning

confidence: 99%

Essential roles of methionine and S -adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis

Berney

Berney-Meyer

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

121

163

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Multidrug resistance, strong side effects, and compliance problems in TB chemotherapy mandate new ways to kill Mycobacterium tuberculosis (Mtb). Here we show that deletion of the gene encoding homoserine transacetylase (metA) inactivates methionine and S-adenosylmethionine (SAM) biosynthesis in Mtb and renders this pathogen exquisitely sensitive to killing in immunocompetent or immunocompromised mice, leading to rapid clearance from host tissues. Mtb ΔmetA is unable to proliferate in primary human macrophages, and in vitro starvation leads to extraordinarily rapid killing with no appearance of suppressor mutants. Cell death of Mtb ΔmetA is faster than that of other auxotrophic mutants (i.e., tryptophan, pantothenate, leucine, biotin), suggesting a particularly potent mechanism of killing. Time-course metabolomics showed complete depletion of intracellular methionine and SAM. SAM depletion was consistent with a significant decrease in methylation at the DNA level (measured by single-molecule real-time sequencing) and with the induction of several essential methyltransferases involved in biotin and menaquinone biosynthesis, both of which are vital biological processes and validated targets of antimycobacterial drugs. Mtb ΔmetA could be partially rescued by biotin supplementation, confirming a multitarget cell death mechanism. The work presented here uncovers a previously unidentified vulnerability of Mtb-the incapacity to scavenge intermediates of SAM and methionine biosynthesis from the host. This vulnerability unveils an entirely new drug target space with the promise of rapid killing of the tubercle bacillus by a new mechanism of action.host-pathogen interaction | bactericidal auxotrophy | amino acid biosynthesis | metabolism U nderstanding the metabolic interactions between an invading microbe and its host is becoming a new cornerstone of host-pathogen research (1-3). Many intracellular pathogens modulate the host response to satisfy their nutritional needs and as a result have become auxotrophic for several essential amino acids and cofactors (4-6). Mycobacterium tuberculosis (Mtb), arguably the most deadly bacterial pathogen in the world (7), adopted a different strategy. This ultra-slow-growing bacterium is prototrophic for all essential cofactors and amino acids, suggesting that it either dwells in host compartments where such metabolites are unavailable or actively chooses this autarkic lifestyle to retain metabolic flexibility and remain invisible to the host. Indeed, much of Mtb's long-term success as a human pathogen is ascribed to its extraordinary stealth in the face of host immunity (8, 9); Mtb's ability to evade detection by the host might explain why devising an efficient vaccine has failed thus far and why drug therapy is difficult. Therefore, understanding Mtb's in vivo metabolic requirements could help in the development of much-needed new strategies for antimycobacterial therapy.Methionine and S-adenosylmethionine (SAM) are essential metabolites that have gained considerable scientific attenti...

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“…The origin of the delay upon methionine removal may therefore also be related to a general growth rate and stress-related signalling mechanism. The molecular details of this global response are currently subject to active research 54,55 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to methionine storage capacity, the regulatory roles of methionine and SAM can also contribute to the observed transcription response delay. Reduction of the intracellular methionine level is perceived by yeast and initiates several stress response mechanisms, such as a growth stop and, eventually, autophagy 54,55 . However, methionine has a particularly complicated role in cell survival and growth control 56 .…”

Section: Discussionmentioning

confidence: 99%

Single yeast cells vary in transcription activity not in delay time after a metabolic shift

Schwabe¹,

Bruggeman²

2014

Nat Commun

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Individual cells respond very differently to changes in environmental conditions. Stochasticity causes cells to respond at different times, magnitudes or both. Here we disentangle and quantify these two sources of heterogeneity. We track the adaptation dynamics of single Saccharomyces cerevisiae cells exposed to a nutrient shift from methionine to sulphate and back. Using single-molecule RNA fluorescence in situ hybridization, we count the number of transcripts of a methionine-biosynthesis enzyme in single cells during adaptation. The variation of response times between cells is small, yet we find a high transient variability in the messenger RNA copy numbers. Surprisingly, single cells display strongly delayed transcription induction, as we could induce transcription fourfold quicker by direct activation and bypassing the cellular control circuitry. Transcription repression occurs rapidly within several minutes. This study indicates that small variability in response timing combined with high, stochastic transcription activity can cause large cell-to-cell variability in dynamic adaptation responses.

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Methionine Inhibits Autophagy and Promotes Growth by Inducing the SAM-Responsive Methylation of PP2A

Cited by 216 publications

References 51 publications

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Essential roles of methionine and S -adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis

Single yeast cells vary in transcription activity not in delay time after a metabolic shift

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