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

Abstract

SummarySensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.

RTH-149 Cell Line, a Useful Tool to Decipher Molecular Mechanisms Related to Fish Nutrition

“…Indeed, in RTH-149 cells, the mTOR appeared to be strongly activated by EAA when the cells were preloaded with glutamine. This observation would indicate that RTH-149 cells sense amino acids and activate the mTOR following mechanisms shared between trout, mice and human cell lines [ 39 , 40 ] Altogether, experiments conducted so far in RTH-149 cells tend to demonstrate that molecular mechanisms leading to GCN2, autophagy and mTOR activation have been conserved throughout evolution.…”

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

“…BioID2 was fused to the C-terminus of DRAM1 without breaking the signal peptide in the N-terminus. The reported DRAM1-interacted proteins such as SLC1A5, SLC7A5 and SLC3A2 7 are also included in the list. Intriguingly, we found that DRAM1 interacted with EPS15 (epidermal growth factor receptor pathway substrate 15), a substrate for the tyrosine kinase of EGFR.…”

“…DNA damage-regulated autophagy modulator 1 (DRAM1) encodes a six transmembrane protein mainly located in lysosomes to induce autophagy and is downregulated in multiple human cancers 6 . DRAM1 directs newly synthesized amino acid transporters to lysosomes and drives lysosomal amino acid efflux 7 . In addition to lysosomes, DRAM1 isoforms are also partly localized to peroxisomes, autophagosomes, and the endoplasmic reticulum 8 .…”

DRAM1 requires PI(3,5)P2generation by PIKfyve to deliver vesicles and their cargo to endolysosomes

“…DRAM1 was shown to interact with the pro-apoptotic protein BAX, which recruited BAX to lysosomes and initiated cell death via release of lysosomal cathepsin B (Guan et al, 2015). Recently, it has also been found that DRAM1 is required for efficient activation of mTORC1, a nutrient-sensing complex that functions at the lysosome (Beaumatin et al, 2019). DRAM1 facilitates activation of mTORC1 by binding the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, thereby directing them to lysosomes (Beaumatin et al, 2019).…”

“…Recently, it has also been found that DRAM1 is required for efficient activation of mTORC1, a nutrient-sensing complex that functions at the lysosome (Beaumatin et al, 2019). DRAM1 facilitates activation of mTORC1 by binding the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, thereby directing them to lysosomes (Beaumatin et al, 2019). An emerging theme is that DRAM1 functions at the interface between lysosomes, signalling complexes, and other vesicles by binding and directing effector molecules.…”