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

Sensing 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. [Display omitted] •DRAM-1 is required for efficient activation of the nutrient-sensing complex mTORC1•DRAM-1 and SCAMP3 direct newly synthesized amino acid transporters to lysosomes•DRAM-1 drives lysosomal amino acid efflux to promote mTORC1 activation•Loss of DRAM-1 increases insulin sensitivity and enhances adipocyte differentiation mTORC1 is a nutrient-sensing complex that affects many cellular processes. Beaumatin et al. show that DRAM-1 and SCAMP3 are required for efficient activation of mTORC1. Consequently, they show that loss of DRAM-1 impairs cell growth and amino-acid-induced autophagy repression while promoting insulin sensitivity, glycemic regulation, and adipocyte differentiation.