Failure of RQC machinery causes protein aggregation and proteotoxic stress

Young-Jun Choe, Sae-Hun Park, Timm Hassemer, Roman Körner, Lisa Vincenz-Donnelly, Manajit Hayer-Hartl and F. Ulrich Hartl ()
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Young-Jun Choe: Max Planck Institute of Biochemistry
Sae-Hun Park: Max Planck Institute of Biochemistry
Timm Hassemer: Max Planck Institute of Biochemistry
Roman Körner: Max Planck Institute of Biochemistry
Lisa Vincenz-Donnelly: Max Planck Institute of Biochemistry
Manajit Hayer-Hartl: Max Planck Institute of Biochemistry
F. Ulrich Hartl: Max Planck Institute of Biochemistry

Nature, 2016, vol. 531, issue 7593, 191-195

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature16973

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