mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Wyant, Gregory A.; Abu-Remaileh, Monther; Wolfson, Rachel L.; Chen, Walter W.; Freinkman, Elizaveta; Danai, Laura V.; Heiden, Matthew G. Vander; Sabatini, David M.

doi:10.1016/j.cell.2017.09.046

Cited by 349 publications

(337 citation statements)

References 56 publications

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“…Fittingly, SLC15a3 and SLC15a4 localize along the length of tubules emanating from phagosomes and macropinosomes . In contrast to SLC15, much more attention has been paid to SLC38a9, the amino acid transporter that also senses arginine and conveys this signal to mTORC1 . Other amino acid transporters are also relevant.…”

Section: Introductionmentioning

confidence: 99%

Resolution of macropinosomes, phagosomes and autolysosomes: Osmotically driven shrinkage enables tubulation and vesiculation

Freeman

Grinstein

2018

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Macropinosomes, phagosomes and autolysosomes are comparatively large, quasi-spherical organelles that play essential functions in immunity and homeostasis. These vacuolar organelles are relatively short-lived, promptly fragmenting into smaller structures. Vacuolar resolution is mediated by tubulation and vesiculation, processes orchestrated by protein complexes that are recruited to highly curved membranes. Importantly, the surface-to-volume ratios of the tubules and vesicles generated during the resolution process are considerably larger than that of the parental vacuole. Because membranes under high hydrostatic tension resist deformation, an active, concomitant loss of volume is required to sustain the resolution process and may even initiate tubulation and vesiculation. Despite its fundamental role in membrane remodeling, the mechanisms that account for organellar volume loss are poorly understood, but are likely to involve the export of solutes followed by osmotically obliged water. In this review, we describe the principles and possible mechanisms underlying the resolution of organelles, with particular attention paid to the osmolytes they contain and the pathways mediating their exit.

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Section: Introductionmentioning

confidence: 99%

Resolution of macropinosomes, phagosomes and autolysosomes: Osmotically driven shrinkage enables tubulation and vesiculation

Freeman

Grinstein

2018

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“…The lysosomal transmembrane protein SLC38A9 interacts with Ragulator (12–14) and is a lysosomal arginine sensor (15), whereas Sestrin2 and CASTOR1 are cytosolic leucine and arginine sensors, respectively, that bind to and inhibit the function of GATOR2 in the absence of their cognate amino acids (16–19). Whether, and how, other amino acids affect mTORC1 signaling is unclear.…”

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confidence: 99%

SAMTOR is an S -adenosylmethionine sensor for the mTORC1 pathway

Orozco

Saxton

et al. 2017

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mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

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“…However, the ability to target autophagy in cancer has also been limited by the high doses of agents such as chloroquine required to elicit an effect in humans , the unpredictable effects of lysosomal inhibitors used to block autophagy on the activity of mTORC1 that is regulated at the lysosome also , the unknown off‐target effects of compounds such as chloroquine and the possible adverse consequences of systemic autophagy inhibition . An additional hurdle to assessing the efficacy of autophagy inhibition in cancer treatment is the lack of reliable markers of autophagy in human tumors .…”

Section: Autophagy In Tumor Stem Cells and Metastatic Dormancymentioning

confidence: 99%

Functions of autophagy in the tumor microenvironment and cancer metastasis

2018

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Macro-autophagy is an ancient and highly conserved self-degradative process that plays a homeostatic role in normal cells by eliminating organelles, pathogens, and protein aggregates. Autophagy, as it is routinely referred to, also allows cells to maintain metabolic sufficiency and survive under conditions of nutrient stress by recycling the by-products of autophagic degradation, such as fatty acids, amino acids, and nucleotides. Tumor cells are more reliant than normal cells on autophagy for survival in part due to their rapid growth rate, altered metabolism, and nutrient-deprived growth environment. How this dependence of tumor cells on autophagy affects their progression to malignancy and metastatic disease is an area of increasing research focus. Here, we review recent work identifying critical functions for autophagy in tumor cell migration and invasion, tumor stem cell maintenance and therapy resistance, and cross-talk between tumor cells and their microenvironment.

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mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Cited by 349 publications

References 56 publications

Resolution of macropinosomes, phagosomes and autolysosomes: Osmotically driven shrinkage enables tubulation and vesiculation

Resolution of macropinosomes, phagosomes and autolysosomes: Osmotically driven shrinkage enables tubulation and vesiculation

SAMTOR is an S -adenosylmethionine sensor for the mTORC1 pathway

Functions of autophagy in the tumor microenvironment and cancer metastasis

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