Abstract
SummaryThe 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.
Highlights
The controlled degradation of proteins by the proteasome is essential in all cells and impairment of the ubiquitin-proteasome system contributes to many pathological conditions (Hershko and Ciechanover, 1998; Finley, 2009)
Because the mechanisms underlying the toxicity resulting from proteasome inhibition are unclear, and as it is unknown whether protein degradation contributes an essential fraction of the intracellular amino acid pool under normal conditions, we examined whether the lethality resulting from proteasome inhibition is mediated by perturbation of amino acid homeostasis
In three model systems—yeast, mammalian cells, and Drosophila—we find that proteasome inhibition causes a lethal shortage of amino acids and the lethality resulting from proteasome inhibition is rescued upon amino acid supplementation, without any detectable decrease in the levels of proteasome substrates in proteasome-inhibited cells
Summary
The controlled degradation of proteins by the proteasome is essential in all cells and impairment of the ubiquitin-proteasome system contributes to many pathological conditions (Hershko and Ciechanover, 1998; Finley, 2009). Because the ubiquitin-proteasome system controls the degradation of a large number of cellular proteins including short-lived, regulatory, and damaged or misfolded proteins (Hershko and Ciechanover, 1998; Schwartz and Ciechanover, 2009), it has been assumed that accumulation of no-longer needed proteins underlies the toxicity of proteasome inhibition. How such proteins become harmful to cells and organisms remains unclear. As selective inhibition of NF-kB does not recapitulate the cytotoxic effects of proteasome inhibition (Hideshima et al, 2002), alternative mechanisms need to be considered
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