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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Article numbere08467
JournaleLife
Volume4
Issue numberSeptember2015
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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