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Failure of RQC machinery causes protein aggregation and proteotoxic stress

Author

Listed:
  • 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)

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.

Suggested Citation

  • Young-Jun Choe & Sae-Hun Park & Timm Hassemer & Roman Körner & Lisa Vincenz-Donnelly & Manajit Hayer-Hartl & F. Ulrich Hartl, 2016. "Failure of RQC machinery causes protein aggregation and proteotoxic stress," Nature, Nature, vol. 531(7593), pages 191-195, March.
    • Handle: RePEc:nat:nature:v:531:y:2016:i:7593:d:10.1038_nature16973
    DOI: 10.1038/nature16973
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    Cited by:

    1. Michelle Lindström & Lihua Chen & Shan Jiang & Dan Zhang & Yuan Gao & Ju Zheng & Xinxin Hao & Xiaoxue Yang & Arpitha Kabbinale & Johannes Thoma & Lisa C. Metzger & Deyuan Y. Zhang & Xuefeng Zhu & Huis, 2022. "Lsm7 phase-separated condensates trigger stress granule formation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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