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NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress

Author

Listed:
  • Chantal M. Maghames

    (Univ. Montpellier, UMR5237)

  • Sofia Lobato-Gil

    (Univ. Montpellier, UMR5237
    ITAV CNRS USR3505, IPBS-UPS)

  • Aurelien Perrin

    (Univ. Montpellier, UMR5237)

  • Helene Trauchessec

    (Univ. Montpellier, UMR5237)

  • Manuel S. Rodriguez

    (ITAV CNRS USR3505, IPBS-UPS)

  • Serge Urbach

    (Institute of Functional Genomics)

  • Philippe Marin

    (Institute of Functional Genomics)

  • Dimitris P. Xirodimas

    (Univ. Montpellier, UMR5237)

Abstract

Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network. Protein modification by the ubiquitin-like molecule NEDD8 increases upon proteotoxic stress and it is characterised by the formation of hybrid NEDD8/ubiquitin conjugates. However, the biological significance of this response is unclear. Combination of quantitative proteomics with biological analysis shows that, during proteotoxic stress, NEDDylation promotes nuclear protein aggregation, including ribosomal proteins as a major group. This correlates with protection of the nuclear Ubiquitin Proteasome System from stress-induced dysfunction. Correspondingly, we show that NEDD8 compromises ubiquitination and prevents targeting and processing of substrates by the proteasome. Moreover, we identify HUWE1 as a key E3-ligase that is specifically required for NEDDylation during proteotoxic stress. The study reveals a specific role for NEDD8 in nuclear protein aggregation upon stress and is consistent with the concept that transient aggregate formation is part of a defence mechanism against proteotoxicity.

Suggested Citation

  • Chantal M. Maghames & Sofia Lobato-Gil & Aurelien Perrin & Helene Trauchessec & Manuel S. Rodriguez & Serge Urbach & Philippe Marin & Dimitris P. Xirodimas, 2018. "NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06365-0
    DOI: 10.1038/s41467-018-06365-0
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    Cited by:

    1. Nathan Riguet & Anne-Laure Mahul-Mellier & Niran Maharjan & Johannes Burtscher & Marie Croisier & Graham Knott & Janna Hastings & Alice Patin & Veronika Reiterer & Hesso Farhan & Sergey Nasarov & Hila, 2021. "Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties," Nature Communications, Nature, vol. 12(1), pages 1-27, December.
    2. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Katrin Stuber & Tobias Schneider & Jill Werner & Michael Kovermann & Andreas Marx & Martin Scheffner, 2021. "Structural and functional consequences of NEDD8 phosphorylation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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