Failure of amino acid homeostasis causes cell death following proteasome inhibition

Suraweera, Amila , Munch, Christian, Hanssum, Ariane, & Bertolotti, Anne (2012) Failure of amino acid homeostasis causes cell death following proteasome inhibition. Molecular Cell, 48(2), 242-253.

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Abstract

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.

Impact and interest:

70 citations in Scopus
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70 citations in Web of Science®

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ID Code: 74397
Item Type: Journal Article
Refereed: Yes
DOI: 10.1016/j.molcel.2012.08.003
ISSN: 1097-4164
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > BIOCHEMISTRY AND CELL BIOLOGY (060100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 24 Jul 2014 05:42
Last Modified: 24 Jul 2014 23:00

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