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

Mol Cell. 2019 Oct 3;76(1):163-176.e8. doi: 10.1016/j.molcel.2019.07.021. Epub 2019 Sep 3.

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.

Keywords: DRAM-1; SCAMP3; amino acid transporters; and adipocyte differentiation; autophagy; insulin signaling; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / enzymology
  • Adipogenesis
  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / metabolism
  • Amino Acid Transport System y+L / genetics
  • Amino Acid Transport System y+L / metabolism
  • Amino Acids / metabolism*
  • Animals
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism*
  • Blood Glucose / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Energy Metabolism*
  • Enzyme Activation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Insulin / blood
  • Large Neutral Amino Acid-Transporter 1 / genetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Lysosomes / enzymology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Protein Transport

Substances

  • Amino Acid Transport System ASC
  • Amino Acid Transport System y+L
  • Amino Acids
  • Atg7 protein, mouse
  • Blood Glucose
  • Carrier Proteins
  • DRAM-1 protein, mouse
  • DRAM1 protein, human
  • Insulin
  • Large Neutral Amino Acid-Transporter 1
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • SCAMP3 protein, human
  • SLC1A5 protein, human
  • SLC7A5 protein, human
  • Slc1a5 protein, mouse
  • Slc7a7 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Autophagy-Related Protein 7