title: A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress.
abstract: The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as ~78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Onn
authors.initials: O
authors.lastname: Brandman
authors.forename: Jacob
authors.initials: J
authors.lastname: Stewart-Ornstein
authors.forename: Daisy
authors.initials: D
authors.lastname: Wong
authors.forename: Adam
authors.initials: A
authors.lastname: Larson
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Williams
authors.forename: Gene-Wei
authors.initials: GW
authors.lastname: Li
authors.forename: Sharleen
authors.initials: S
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: King
authors.forename: Peter S
authors.initials: PS
authors.lastname: Shen
authors.forename: Jimena
authors.initials: J
authors.lastname: Weibezahn
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Dunn
authors.forename: Silvi
authors.initials: S
authors.lastname: Rouskin
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Inada
authors.forename: Adam
authors.initials: A
authors.lastname: Frost
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C067168:HSF1 protein, S cerevisiae; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D010455:Peptides; D016601:RNA-Binding Proteins; C577644:Rqc1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C577643:Tae2 protein, S cerevisiae; D014157:Transcription Factors; C552998:Ltn1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein