title: Failure of RQC machinery causes protein aggregation and proteotoxic stress.
abstract: Translation of messenger RNAs lacking a stop codon results in the addition of a carboxy-terminal poly-lysine tract to the nascent polypeptide, causing ribosome stalling. Non-stop proteins and other stalled nascent chains are recognized by the ribosome quality control (RQC) machinery and targeted for proteasomal degradation. Failure of this process leads to neurodegeneration by unknown mechanisms. Here we show that deletion of the E3 ubiquitin ligase Ltn1p in yeast, a key RQC component, causes stalled proteins to form detergent-resistant aggregates and inclusions. Aggregation is dependent on a C-terminal alanine/threonine tail that is added to stalled polypeptides by the RQC component, Rqc2p. Formation of inclusions additionally requires the poly-lysine tract present in non-stop proteins. The aggregates sequester multiple cytosolic chaperones and thereby interfere with general protein quality control pathways. These findings can explain the proteotoxicity of ribosome-stalled polypeptides and demonstrate the essential role of the RQC in maintaining proteostasis.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Choe
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Sae-Hun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Hassemer
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Körner
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Vincenz-Donnelly
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Manajit
authors.initials: M
authors.lastname: Hayer-Hartl
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
mesh_terms: D000409:Alanine / Q000378:metabolism; D018388:Codon, Terminator / Q000235:genetics; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D011107:Polylysine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D014176:Protein Biosynthesis; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D013912:Threonine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; D018832:Molecular Chaperones; D066329:Protein Aggregates; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C577643:Tae2 protein, S cerevisiae; D011107:Polylysine; D013912:Threonine; C552998:Ltn1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000409:Alanine