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

eLife

Susan Lindquist¹  Ferdy R van Diemen²  Thijn R Brummelkamp²  Marc L Mendillo³  Alfred L Goldberg⁴  Jinghui Zhao⁴  Jan E Carette⁵  Parker H Merrill⁶  Domagoj Cikes⁷  Josef M Penninger⁷  Sandro Santagata⁸  Peter Tsvetkov⁸  Malini Varadarajan⁸ 

[1] Department of Pathology, Brigham and Women's Hospital, Boston, United States;Department of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands;Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States;Department of Cell Biology, Harvard Medical School, Boston, United States;Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States;Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria;Whitehead Institute for Biomedical Research, Cambridge, United States;

关键词: proteasome;    bortezomib;    HSF1;    MG132;    heat-shock;   

DOI  :  10.7554/eLife.08467

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown