Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome.
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.
Whitehead Institute for Biomedical Research, Cambridge, United States.
Peter
P
Tsvetkov
Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States.
Marc L
ML
Mendillo
Department of Cell Biology, Harvard Medical School, Boston, United States.
Jinghui
J
Zhao
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
Jan E
JE
Carette
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Parker H
PH
Merrill
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
Domagoj
D
Cikes
Whitehead Institute for Biomedical Research, Cambridge, United States.
Malini
M
Varadarajan
Department of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.
Ferdy R
FR
van Diemen
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
Josef M
JM
Penninger
Department of Cell Biology, Harvard Medical School, Boston, United States.
Alfred L
AL
Goldberg
Department of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.
Thijn R
TR
Brummelkamp
Whitehead Institute for Biomedical Research, Cambridge, United States.
Sandro
S
Santagata
Whitehead Institute for Biomedical Research, Cambridge, United States.
Susan
S
Lindquist
D002460:Cell Line; D002470:Cell Survival; D004847:Epithelial Cells / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
D046988:Proteasome Endopeptidase Complex
HSF1; MG132; S. cerevisiae; bortezomib; cell biology; heat-shock; human; human biology; medicine; proteasome