DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux

Beaumatin, F. et al. (2019) DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux. Molecular Cell, 76(1), 163-176.E8. (doi: 10.1016/j.molcel.2019.07.021) (PMID:31492633) (PMCID:PMC6892261)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Long, Dr Jaclyn and Barthet, Valentin and Ryan, Professor Kevin and O'Prey, Mr James and Nixon, Mr Colin and Tait, Professor Stephen and Lopez, Dr Jonathan and O'Prey, Mrs Margaret and Beaumatin, Dr Florian and Parvy, Dr Jean-Philippe
• Authors: Beaumatin, F., O'Prey, J., Barthet, V. J.A., Zunino, B., Parvy, J.-P., Bachmann, A. M., O'Prey, M., Kania, E., Gonzalez, P. S., Macintosh, R., Lao, L. Y., Nixon, C., Lopez, J., Long, J. S., Tait, S. W.G., and Ryan, K. N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cell
• Publisher: Elsevier
• ISSN: 1097-2765
• ISSN (Online): 1097-4164
• Published Online: 03 September 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Molecular Cell 76(1):163-176.E8
• Publisher Policy: Reproduced under a Creative Commons License