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

Peter Tsvetkov,Malini Varadarajan,Jan E Carette,Parker H Merrill,Alfred L Goldberg,Thijn R Brummelkamp,Domagoj Cikes,Jinghui Zhao,Josef M Penninger,Marc L Mendillo,Susan Lindquist,Sandro Santagata,Ferdy R Van Diemen

doi:10.7554/elife.08467

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.

Highlights

Maintaining the integrity of the proteome is vital for all cells
Protein chaperone systems and the ubiquitin-proteasome pathway are essential components of the global architecture that sustains protein homeostasis. The importance of these systems is underscored by the fact that perturbation of protein homeostasis is central to diverse human diseases (Balch et al, 2008; Labbadia and Morimoto, 2015)
We find that bortezomib treatment leads to a sharp decrease in the levels of proteasome complexes

Summary

Introduction

Protein chaperone systems and the ubiquitin-proteasome pathway are essential components of the global architecture that sustains protein homeostasis. The importance of these systems is underscored by the fact that perturbation of protein homeostasis is central to diverse human diseases (Balch et al, 2008; Labbadia and Morimoto, 2015). Malignant cells co-opt protein quality control systems to accommodate the severe proteotoxic stresses that arise from high mutation loads, relentless biomass accumulation and protein turnover (Mendillo et al, 2012; Deshaies, 2014; Scherz-Shouval et al, 2014). Because the ubiquitin-proteasome system is the major mechanism regulating protein turnover, cells are highly vulnerable to insults that impair the function of this system

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