Mol. Cell, published online 5 September 2012; doi:10.1016/j.molcel.2012.08.003

The proteasome degrades many cellular proteins, and proteasome inhibitors induce cancer cell death, but the mechanism underlying inhibitor-mediated death is not known. Suraweera et al. now show that temperature-sensitive proteasome inhibition in yeast leads to a decrease in the amount of free amino acids and that supplementation of proteasome-inhibited yeast cells with amino acids can rescue the lethality associated with proteasome inhibition without promoting proteasome activity. The authors also showed that treatment of mammalian cells with small-molecule proteasome inhibitors led to a decrease in the amount of select amino acids, including cysteine, asparagine and aspartate. Amino acid supplementation increased cell survival in a dose-dependent manner in response to inhibitors without rescuing either proteasome activity or blocking inhibitor function. Proteasome inhibitors induce the integrated stress response and autophagy in treated cells, and cysteine supplementation was sufficient to decrease the induction of these pathways. Blocking amino acid consumption through protein synthesis with cyclohexamide was sufficient to counter the drop in the amount of amino acids and to decrease inhibitor-induced lethality. Inhibitor-induced amino acid shortage was also observed in Drosophila, and amino acid supplementation could rescue lethality in treated flies. Taken together, these data indicate that amino acid scarcity is the signal that leads to stress responses and ultimately cell death in multiple species.