Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response.
Stress responses are adaptive cellular programs that identify and mitigate potentially dangerous threats. Misfolded proteins are a ubiquitous and clinically relevant stress. Trivalent metalloids, such as arsenic, have been proposed to cause protein misfolding. Using tandem mass tag-based mass spectrometry, we show that trivalent arsenic results in widespread reorganization of the cell from an anabolic to a catabolic state. Both major pathways of protein degradation, the proteasome and autophagy, show increased abundance of pathway components and increased functional output, and are required for survival. Remarkably, cells also showed a down-regulation of ribosomes at the protein level. That this represented an adaptive response and not an adverse toxic effect was indicated by enhanced survival of ribosome mutants after arsenic exposure. These results suggest that a major source of toxicity of trivalent arsenic derives from misfolding of newly synthesized proteins and identifies ribosome reduction as a rapid, effective, and reversible proteotoxic stress response.
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Angel
A
Guerra-Moreno
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, and.
Marta
M
Isasa
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Meera K
MK
Bhanu
Rosenstiel Basic Medical Sciences Research Center and the Department of Biology, Brandeis University, Waltham, Massachusetts 02254.
David P
DP
Waterman
Rosenstiel Basic Medical Sciences Research Center and the Department of Biology, Brandeis University, Waltham, Massachusetts 02254.
Vinay V
VV
Eapen
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, and.
Steven P
SP
Gygi
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, jwhanna@partners.org.
John
J
Hanna
D018053:Arsenites / Q000633:toxicity*; D040901:Proteomics; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013312:Stress, Physiological
D018053:Arsenites; C015001:arsenite
autophagy; proteasome; proteostasis; ribosome; stress response