Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

ELife
Peter TsvetkovSusan Lindquist

Abstract

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

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Citations

Dec 17, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jinghui ZhaoAlfred Lewis Goldberg
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Datasets Mentioned

BETA
PRJNA281714
PRJNA281613

Methods Mentioned

BETA
environmental stresses
gene-trap
FACS
Genotyping
PCR
electrophoresis
RNA-seq
fluorescence-activated
fluorescence microscopy
Illumina sequencing

Software Mentioned

Imagelab
Bowtie
cuffdiff
GSEA
TopHat
GOrilla
Fiji
SAMtools
cuffnorm
MACSQuant

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