Failure of amino acid homeostasis causes cell death following proteasome inhibition

Mol Cell. 2012 Oct 26;48(2):242-53. doi: 10.1016/j.molcel.2012.08.003. Epub 2012 Sep 6.


The ubiquitin-proteasome system targets many cellular proteins for degradation and thereby controls most cellular processes. Although it is well established that proteasome inhibition is lethal, the underlying mechanism is unknown. Here, we show that proteasome inhibition results in a lethal amino acid shortage. In yeast, mammalian cells, and flies, the deleterious consequences of proteasome inhibition are rescued by amino acid supplementation. In all three systems, this rescuing effect occurs without noticeable changes in the levels of proteasome substrates. In mammalian cells, the amino acid scarcity resulting from proteasome inhibition is the signal that causes induction of both the integrated stress response and autophagy, in an unsuccessful attempt to replenish the pool of intracellular amino acids. These results reveal that cells can tolerate protein waste, but not the amino acid scarcity resulting from proteasome inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Amino Acids / physiology
  • Animals
  • Autophagy*
  • Cell Death / physiology
  • Drosophila melanogaster / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Proteasome Endopeptidase Complex* / metabolism
  • Proteasome Endopeptidase Complex* / physiology
  • Proteolysis*
  • Saccharomyces cerevisiae / metabolism
  • Signal Transduction
  • Ubiquitin / metabolism


  • Amino Acids
  • Ubiquitin
  • Proteasome Endopeptidase Complex