THE ROLE OF AUTOPHAGY AND CYSTINE IN THE REGULATION OF AMINO ACID SIGNALING PATHWAYS

Abstract

Deficiency of amino acids is monitored at the cellular level by amino acid signaling pathways including the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the integrated stress response (ISR). We investigated their specific responses under different amino acid-restricted conditions. We found that in C2C12 mouse myotubes, mTORC1 signaling was sustained under the deprivation of all amino acids, and this was attributable to autophagy, which generated amino acids to maintain mTORC1 signaling. The ISR, however, was negatively regulated by autophagy independent of amino acids in this system. In HepG2 hepatoma cells, the deprivation of cystine progressively suppressed mTORC1 signaling and acutely induced the ISR, and glutathione protected against these stresses through its release of cysteine via extracellular degradation. Furthermore, the depletion of both cysteine and GSH resulted in ferroptosis. Altogether, our studies showed that the signaling effect of amino acid limitation is context-dependent.