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  Failure of RQC machinery causes protein aggregation and proteotoxic stress

Choe, Y.-J., Park, S.-H., Hassemer, T., Körner, R., Vincenz-Donnelly, L., Hayer-Hartl, M., et al. (2016). Failure of RQC machinery causes protein aggregation and proteotoxic stress. Nature, 531(7593), 191-195. doi:10.1038/nature16973.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-2C43-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-0E9A-8
Genre: Journal Article

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 Creators:
Choe, Young-Jun1, Author              
Park, Sae-Hun1, Author              
Hassemer, Timm1, Author              
Körner, Roman1, Author              
Vincenz-Donnelly, Lisa1, Author              
Hayer-Hartl, Manajit2, Author              
Hartl, F. Ulrich1, Author              
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2Hayer-Hartl, Manajit / Chaperonin-assisted Protein Folding, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565153              

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Free keywords: QUALITY-CONTROL COMPLEX; UBIQUITIN-PROTEASOME-SYSTEM; MESSENGER-RNA SURVEILLANCE; SACCHAROMYCES-CEREVISIAE; SUBUNIT DISSOCIATION; BUDDING YEAST; RIBOSOME; DEGRADATION; TRANSLATION; CHAPERONE
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: ISI: 000371665100032
DOI: 10.1038/nature16973
 Degree: -

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Project name : Toxic Protein AGgregation in Neurodegeneration (ToPAG) ERC-2012-SyG
Grant ID : 318987
Funding program : Funding Programme 7 (FP7)
Funding organization : European Commission (EC)

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 531 (7593) Sequence Number: - Start / End Page: 191 - 195 Identifier: ISSN: 0028-0836
CoNE: /journals/resource/954925427238