mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

Villa, Elodie; Sahu, Umakant; O’Hara, Brendan P.; Ali, Eunüs S.; Helmin, Kathryn A.; Asara, John M.; Gao, Peng; Singer, Benjamin D.; Ben-Sahra, Issam

doi:10.1016/j.molcel.2021.03.009

Cited by 108 publications

(79 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unbiased metabolomics and subsequent metabolic flux analyses demonstrated that the hepatocyte insulin-mTORC1-ATF4 pathway stimulates SAM production within the methionine cycle, as well as the transsulfuration pathway, which shunts off of the methionine cycle. While a recent study demonstrated that mTORC1 regulates SAM synthesis in proliferating cells through c-Myc-dependent control of Mat2a expression [48], the levels of transcripts encoding the MAT enzymes were unaffected by insulin signaling in hepatocytes. Hepatic MAT activity can also be attenuated by reactive oxygen species [46], which are elevated in other models of ATF4 deficiency [22].…”

Section: Discussionmentioning

confidence: 94%

“…Genes of the cytosolic THF and methionine cycles were insensitive to insulin and ATF4 depletion in primary hepatocytes (Figure 5D). Notably, the MAT enzymes were not found to be transcriptionally regulated in this setting, in contrast to proliferating cells, where MAT2A has recently been found to be regulated by mTORC1 signaling via c-Myc [48]. Interestingly, only Cth, encoding an enzyme of the transsulfuration pathway, also known as cystathionine gamma lyase (CGL), was found to be significantly induced with insulin in an ATF4-dependent manner (Figure 5D).…”

Section: Atf4 Regulates Methionine Metabolism In Hepatocytesmentioning

confidence: 89%

See 1 more Smart Citation

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Byles

Cormerais

Kalafut

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Objective: The mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism. Methods: ATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor rapamycin. Primary hepatocytes from wild-type or liver-specific Atf4 knockout (LAtf4KO) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versus LAtf4KO mice. Results: We demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver in response to feeding and in a hepatocyte-intrinsic manner by insulin. While we demonstrate that de novo purine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of non-essential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine. Conclusion: The results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Atf4 Regulates Methionine Metabolism In Hepatocytesmentioning

confidence: 89%

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Byles

Cormerais

Kalafut

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genes of the cytosolic THF and methionine cycles were insensitive to insulin and ATF4 depletion in primary hepatocytes ( Figure 5 D). Notably, the MAT enzymes were not found to be transcriptionally regulated in this setting, in contrast to proliferating cells, where MAT2A has recently been found to be regulated by mTORC1 signaling through c-Myc [ 54 ]. Interestingly, only Cth , encoding an enzyme of the transsulfuration pathway, also known as cystathionine gamma-lyase (CGL), was found to be significantly induced with insulin in an ATF4-dependent manner ( Figure 5 D).…”

Section: Resultsmentioning

confidence: 99%

“…Unbiased metabolomics and subsequent metabolic flux analyses demonstrated that the hepatocyte insulin-mTORC1-ATF4 pathway stimulates SAM production within the methionine cycle, along with the transsulfuration pathway, which shunts off of the methionine cycle. While a recent study demonstrated that mTORC1 regulates SAM synthesis in proliferating cells through c-Myc-dependent control of Mat2a expression [ 54 ], the levels of transcripts encoding the MAT enzymes were unaffected by insulin signaling in hepatocytes. Hepatic MAT activity can also be attenuated by reactive oxygen species [ 52 ], which are elevated in other models of ATF4 deficiency [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Byles

Cormerais

Kalafut

et al. 2021

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

Objective The mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism. Methods ATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor, rapamycin. Primary hepatocytes from wild-type or liver-specific Atf4 knockout ( LAtf4 KO ) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versus LAtf4 KO mice. Results We demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver, in a hepatocyte-intrinsic manner by insulin in response to feeding. While we demonstrate that de novo purine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of nonessential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine. Conclusions The results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in the liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.

show abstract

“…Nonetheless, these data strongly suggest a direct and/or indirect role for mTORC1 in regulating Amd1 expression during MTE-induced muscle hypertrophy. Interestingly, it has recently been shown that mTORC1, via c-Myc, also positively regulates the expression of the enzyme, MAT2A, which catalyzes the conversion of methionine to SAM (S-adenosylmethione), the product of one-carbon metabolism and the substrate for Amd1 (52). Furthermore, SAM is a known indirect activator of mTORC1 activity via binding to the protein, SAMTOR (53).…”

Section: Discussionmentioning

confidence: 99%

The regulation of polyamine pathway proteins in models of skeletal muscle hypertrophy and atrophy: a potential role for mTORC1

Tabbaa

Gomez

Campelj

et al. 2021

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Polyamines have been shown to be absolutely required for protein synthesis and cell growth. The serine/threonine kinase, the mechanistic target of rapamycin complex 1 (mTORC1), also plays a fundamental role in the regulation of protein turnover and cell size, including in skeletal muscle, where mTORC1 is sufficient to increase protein synthesis and muscle fiber size, and is necessary for mechanical overload-induced muscle hypertrophy. Recent evidence suggests that mTORC1 may regulate the polyamine metabolic pathway, however, there is currently no evidence in skeletal muscle. This study examined changes in polyamine pathway proteins during muscle hypertrophy induced by mechanical overload (7 days), with and without the mTORC1 inhibitor, rapamycin, and during muscle atrophy induced by food deprivation (48 h) and denervation (7 days) in mice. Mechanical overload induced an increase in mTORC1 signaling, protein synthesis and muscle mass, and these were associated with rapamycin-sensitive increases in adenosylmethione decarboxylase 1 (Amd1), spermidine synthase (SpdSyn), and c-Myc. Food deprivation decreased mTORC1 signaling, protein synthesis, and muscle mass, accompanied by a decrease in spermidine/spermine acetyltransferase 1 (Sat1). Denervation, resulted increased mTORC1 signaling and protein synthesis, and decreased muscle mass, which was associated with an increase in SpdSyn, spermine synthase (SpmSyn), and c-Myc. Combined, these data show that polyamine pathway enzymes are differentially regulated in models of altered mechanical and metabolic stress, and that Amd1 and SpdSyn are, in part, regulated in a mTORC1-dependent manner. Furthermore, these data suggest that polyamines may play a role in the adaptive response to stressors in skeletal muscle.

show abstract

mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

Cited by 108 publications

References 104 publications

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

The regulation of polyamine pathway proteins in models of skeletal muscle hypertrophy and atrophy: a potential role for mTORC1

Contact Info

Product

Resources

About