Recent advances in understanding of amino acid signaling to mTORC1 activation

10.2741/4762 ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 971-982 ◽  
Author(s):  
Shanping He
Keyword(s):  
Amino Acid ◽  
Recent Advances ◽  
Mtorc1 Activation ◽  
Amino Acid Signaling

Recent advances in amino acid analysis by capillary electromigration methods: June 2015-May 2017

2017 ◽  
Vol 39 (1) ◽  
pp. 190-208 ◽  
Author(s):  
Véréna Poinsot ◽  
Varravaddheay Ong-Meang ◽  
Audrey Ric ◽  
Pierre Gavard ◽  
Lucie Perquis ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Analysis ◽  
Recent Advances

scholarly journals Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Rituraj Pal ◽  
Michela Palmieri ◽  
Arindam Chaudhury ◽  
Tiemo Jürgen Klisch ◽  
Alberto di Ronza ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rag Gtpase ◽  
Mtorc1 Activation

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

2020 ◽  
Author(s):  
Ada Nowosad ◽  
Pauline Jeannot ◽  
Caroline Callot ◽  
Justine Creff ◽  
Renaud T. Perchey ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Underlying Mechanism ◽  
Mtor Inhibition ◽  
Mtorc1 Signaling ◽  
And Function ◽  
Mtorc1 Activation ◽  
Catabolic Process ◽  
Mtor Activity ◽  
Dependent Mechanism

SummaryAutophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies have shown that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy. However, the underlying mechanism remains unknown. Here, we report that in amino acid deprived cells, p27 controls autophagy via an mTORC1-dependent mechanism. During prolonged amino acid starvation, a fraction of p27 is recruited to lysosomes where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 lysosomal localization and activation. p27 binding to LAMTOR1 prevents Ragulator assembly and function and subsequent mTORC1 activation, thereby promoting autophagy. Conversely, upon amino acid withdrawal, p27−/− cells exhibit elevated mTORC1 signaling, impaired lysosomal activity and autophagy, and resistance to apoptosis. This is associated with sequestration of TFEB in the cytoplasm, preventing the induction of lysosomal genes required for lysosomal function. Silencing of LAMTOR1 or mTOR inhibition restores autophagy and induces apoptosis in p27−/− cells. Together, these results reveal a direct, coordinated regulation between the cell cycle and cell growth machineries.

scholarly journals PAT2 regulates autophagy through vATPase assembly and lysosomal acidification in brown adipocytes

2020 ◽  
Author(s):  
Jiefu Wang ◽  
Martin Krueger ◽  
Stefanie M. Hauck ◽  
Siegfried Ussar
Keyword(s):  
Amino Acid ◽  
Brown Adipocyte ◽  
Amino Acid Transporters ◽  
Mitochondrial Uncoupling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Glucose And Lipid Homeostasis ◽  
Mtorc1 Activation ◽  
Lysosomal Acidification

Brown adipose tissue (BAT) plays a key role in maintaining body temperature as well as glucose and lipid homeostasis by its ability to dissipate energy through mitochondrial uncoupling. To facilitate these tasks BAT needs to adopt its thermogenic activity and substrate utilization to changes in nutrient availability, regulated by a complex network of neuronal, endocrine and nutritional inputs. Amongst this multitude of factors influencing BAT activity changes in the autophagic response of brown adipocytes are an important regulator of its thermogenic capacity and activity. Increasing evidence supports an important role of amino acid transporters in mTORC1 activation and the regulation of autophagy. However, a specific role of amino acid transporters in BAT regulating its function has not been described. Here we show that the brown adipocyte specific proton coupled amino acid transporter PAT2 rapidly translocates from the plasma membrane to the lysosome in response to amino acid withdrawal, where it facilitates the assembly of the lysosomal vATPase. Loss or overexpression of PAT2 therefore impair lysosomal acidification, autophagolysosome formation and starvation induced mTORC1 activation.

scholarly journals mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux

2019 ◽  
Vol 76 (1) ◽  
pp. 163-176.e8 ◽  
Author(s):  
Florian Beaumatin ◽  
Jim O’Prey ◽  
Valentin J.A. Barthet ◽  
Barbara Zunino ◽  
Jean-Philippe Parvy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Efflux ◽  
Mtorc1 Activation

scholarly journals ATF4-Mediated Upregulation of REDD1 and Sestrin2 Suppresses mTORC1 Activity during Prolonged Leucine Deprivation

2019 ◽  
Vol 150 (5) ◽  
pp. 1022-1030 ◽  
Author(s):  
Dandan Xu ◽  
Weiwei Dai ◽  
Lydia Kutzler ◽  
Holly A Lacko ◽  
Leonard S Jefferson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Dna Damage ◽  
Amino Acid ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Dependent Manner ◽  
Mouse Embryo Fibroblasts ◽  
Damage Response ◽  
Mtorc1 Activation ◽  
In Cells

ABSTRACT Background The protein kinase target of rapamycin (mTOR) in complex 1 (mTORC1) is activated by amino acids and in turn upregulates anabolic processes. Under nutrient-deficient conditions, e.g., amino acid insufficiency, mTORC1 activity is suppressed and autophagy is activated. Intralysosomal amino acids generated by autophagy reactivate mTORC1. However, sustained mTORC1 activation during periods of nutrient insufficiency would likely be detrimental to cellular homeostasis. Thus, mechanisms must exist to prevent amino acids released by autophagy from reactivating the kinase. Objective The objective of the present study was to test whether mTORC1 activity is inhibited during prolonged leucine deprivation through ATF4-dependent upregulation of the mTORC1 suppressors regulated in development and DNA damage response 1 (REDD1) and Sestrin2. Methods Mice (8 wk old; C57Bl/6 × 129SvEV) were food deprived (FD) overnight and one-half were refed the next morning. Mouse embryo fibroblasts (MEFs) deficient in ATF4, REDD1, and/or Sestrin2 were deprived of leucine for 0–16 h. mTORC1 activity and ATF4, REDD1, and Sestrin2 expression were assessed in liver and cell lysates. Results Refeeding FD mice resulted in activation of mTORC1 in association with suppressed expression of both REDD1 and Sestrin2 in the liver. In cells in culture, mTORC1 exhibited a triphasic response to leucine deprivation, with an initial suppression followed by a transient reactivation from 2 to 4 h and a subsequent resuppression after 8 h. Resuppression occurred concomitantly with upregulated expression of ATF4, REDD1, and Sestrin2. However, in cells lacking ATF4, neither REDD1 nor Sestrin2 expression was upregulated by leucine deprivation, and resuppression of mTORC1 was absent. Moreover, in cells lacking either REDD1 or Sestrin2, mTORC1 resuppression was attenuated, and in cells lacking both proteins resuppression was further blunted. Conclusions The results suggest that leucine deprivation upregulates expression of both REDD1 and Sestrin2 in an ATF4-dependent manner, and that upregulated expression of both proteins is involved in resuppression of mTORC1 during prolonged leucine deprivation.

Sign in / Sign up

Export Citation Format

Share Document