Phospholipase D–dependent mTOR complex 1 (mTORC1) activation by glutamine

Bernfeld, Elyssa; Menon, Deepak; Vaghela, Vishaldeep; Zerin, Ismat; Faruque, Promie; Frías, María A.; Foster, David A.

doi:10.1074/jbc.ra118.004972

Cited by 46 publications

(28 citation statements)

References 40 publications

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“…In full medium, LAMTOR1 silencing did not affect mTORC1 activation levels (Fig. 7E), consistent with Rag and Ragulator-independent pathways mediating mTORC1 activation, as reported previously 79, 80 . However, upon aa deprivation, LAMTOR1 knockdown in p27 −/− MEFs restored mTOR inhibition, evaluated by measuring p70 S6K1 phosphorylation levels (Fig.…”

Section: Resultssupporting

confidence: 91%

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

Nowosad

Jeannot

Callot

et al. 2020

Preprint

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22 Tel: +33 (0)561558486 23 24 25 26 2 Summary 27Autophagy is a catabolic process whereby cytoplasmic components are degraded within 28 lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several 29 studies have shown that the CDK inhibitor p27 Kip1 promotes starvation-induced autophagy. 30 However, the underlying mechanism remains unknown. Here, we report that in amino acid 31 deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During 32 prolonged amino acid starvation, a fraction of p27 is recruited to lysosomes where it interacts 33 with LAMTOR1, a component of the Ragulator complex required for mTORC1 lysosomal 34 localization and activation. p27 binding to LAMTOR1 prevents Ragulator assembly and function 35 and subsequent mTORC1 activation, thereby promoting autophagy. Conversely, upon amino 36 acid withdrawal, p27 -/cells exhibit elevated mTORC1 signaling, impaired lysosomal activity 37 and autophagy, and resistance to apoptosis. This is associated with sequestration of TFEB in the 38 cytoplasm, preventing the induction of lysosomal genes required for lysosomal function. 39 Silencing of LAMTOR1 or mTOR inhibition restores autophagy and induces apoptosis in p27 -/-40 cells. Together, these results reveal a direct, coordinated regulation between the cell cycle and 41 cell growth machineries. 42 43 44 45 46 47In all organisms, cell growth is coupled to cell division to allow normal development and 48 maintain homeostasis. How cells coordinate the machinery that regulates cell growth, at the heart 49 of which lies the mTOR kinase, with the machinery that controls cell division, driven by 50 cyclin/CDK complexes, has been the subject of considerable interest for several decades 1 . This 51 coordination has been mostly studied under normal metabolic conditions and except for notable 52 exceptions, such as early embryonic development, it appears that growth control drives the 53 activity of the cell cycle machinery. Here we investigated this question in conditions of 54 metabolic restriction to determine if the cell cycle machinery could in turn regulate the growth 55 control machinery. 56 p27 Kip1 (p27) was initially identified as a cyclin/CDK inhibitor 2, 3 . Due to its ability to induce 57 cell cycle arrest, p27 acts as a tumor suppressor and p27 -/mice display multiple organ 58 hyperplasia and spontaneously develop pituitary tumors 4 . Nevertheless, in contrast to classic 59 tumor suppressors such as p53 or Rb, inactivating mutations of the p27 gene are extremely rare 60 and its inactivation in cancer is rather caused by enhanced degradation, attenuated transcription 61 or translation, or mislocalization in the cytoplasm 2, 3, 5 . The latter correlates with poor prognosis 62 in a variety of cancers, suggesting a direct contribution of cytoplasmic p27 to tumor progression 2, 63 3 . In fact, knock-in mice in which p27 is largely sequestered in the nucleus due to defective 64 export to the cytoplasm (p27 S10A ) are partially resistant to tumorigene...

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Section: Resultssupporting

confidence: 91%

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

Nowosad

Jeannot

Callot

et al. 2020

Preprint

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“…On the other hand, a recent study suggested that the addition of dimethyl-α-KG (DM-α-KG), a cell-permeable analog of α-KG, promotes mTORC1 activation even in RAGA/B knockout cells. Moreover, the effect of DM-α-KG on mTORC1 was counteracted by PLD1 inhibition, indicating that α-KG stimulates mTORC1 via the PLD1-RalA-Arf1 axis in addition to RagB [127].…”

Section: Glutamine-dependent Activation Of Mtorc1 Via Arf1 In the Golmentioning

confidence: 98%

“…3 a). Although the mechanisms by which Arf1 induces mTORC1 translocation to the lysosomes are largely unknown, a recent report suggested that phosphatidic acid (PA) generated by the phospholipase D1 (PLD1) acts downstream of Arf1 to promote mTORC1 activation [ 127 ]. Indeed, PLD1 activity appears to be regulated by leucine and more potently by glutamine.…”

Section: Main Textmentioning

confidence: 99%

“…PA produced by PLD1 appears to act as an important, closely upstream mediator of mTORC1 activation. In fact, although RHEB knockdown resulted in decreased PLD1 and mTORC1 activity, exogenous addition of PA could rescue decreased S6K1 phosphorylation in RHEB knockdown cells, suggesting that PA acts downstream of Rheb [ 127 ]. Indeed, previous reports suggested that PA directly binds to mTORC1, thus promoting its kinase activity in vitro [ 130 ], and induces the dissociation of the inhibitory subunit DEPTOR from mTORC1 to promote the activation of the complex [ 131 ].…”

Section: Main Textmentioning

confidence: 99%

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Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes

et al. 2020

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The mechanistic target of rapamycin complex 1 (mTORC1) is an essential regulator of cell growth and metabolism through the modulation of protein and lipid synthesis, lysosome biogenesis, and autophagy. The activity of mTORC1 is dynamically regulated by several environmental cues, including amino acid availability, growth factors, energy levels, and stresses, to coordinate cellular status with environmental conditions. Dysregulation of mTORC1 activity is closely associated with various diseases, including diabetes, cancer, and neurodegenerative disorders. The discovery of Rag GTPases has greatly expanded our understanding of the regulation of mTORC1 activity by amino acids, especially leucine and arginine. In addition to Rag GTPases, other factors that also contribute to the modulation of mTORC1 activity have been identified. In this review, we discuss the mechanisms of regulation of mTORC1 activity by particular amino acids.

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“…Although it has been reported some channel proteins and metabolic enzymes including IDH1, IDH2, BCAT1, OGDH, GDH, SLC1A4, SLC1A5, GLUL, and GLA were involved in the metabolism of α-ketoglutarate in many cell types [9,[23][24][25][26][27][28][29][30][31], the mechanism of intracellular α-ketoglutarate regulation during HSC activation has not been previously reported. The main metabolic sources of intracellular α-ketoglutarate including glucose and glutamine were kept sufficient in the cell culture medium in our research [32,33], while the expression of channel proteins and metabolic enzymes mentioned above were investigated during HSC activation.…”

Section: Discussionmentioning

confidence: 97%

The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation

et al. 2020

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Background: The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis. α-ketoglutarate is a natural metabolite and previous studies have shown that increase in intracellular α-ketoglutarate can inhibit HSC activation. Aim: The aim of the present study is to determine the changes and role of intracellular α-ketoglutarate in HSC activation and clarify its mechanism of action. Methods: A human HSC cell line (LX-2) and the primary mouse HSC were used in the present study. We detected the changes of intracellular α-ketoglutarate levels and the expression of enzymes involved in the metabolic processes during HSC activation. We used siRNA to determine the role of intracellular α-ketoglutarate in HSC activation and elucidate the mechanism of the metabolic changes. Results: Our results demonstrated that intracellular α-ketoglutarate levels decreased with an HSC cell line and primary mouse HSC activation, as well as the expression of isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the production of α-ketoglutarate. In addition, knockdown of IDH2 efficiently promoted the activation of HSCs, which was able to be reversed by introduction of an α-ketoglutarate analogue. Furthermore, we demonstrated that α-ketoglutarate regulated HSC activation is independent of transforming growth factor-β1 (TGF-β1). Conclusions: Our findings demonstrated that decrease in IDH2 expression limits the production of α-ketoglutarate during HSC activation and in turn promotes the activation of HSCs through a TGF-β1 independent pathway. The present study suggests that IDH2 and α-ketoglutarate may be potential new targets for the prevention and treatment of liver fibrosis.

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Phospholipase D–dependent mTOR complex 1 (mTORC1) activation by glutamine

Cited by 46 publications

References 40 publications

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

p27 regulates the autophagy-lysosomal pathway via the control of Ragulator and mTOR activity in amino acid deprived cells

Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes

The mechanism and role of intracellular α-ketoglutarate reduction in hepatic stellate cell activation

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