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Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates

Author

Listed:
  • Leo Kiss

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue
    Max Planck Institute of Biochemistry)

  • Tyler Rhinesmith

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Jakub Luptak

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Claire F. Dickson

    (EMBL Australia Node in Single Molecule Science and ARC Centre of Excellence in Advanced Molecular Imaging School of Medical Sciences)

  • Jonas Weidenhausen

    (Biochemiezentrum der Universität Heidelberg (BZH), INF328
    EMBL Heidelberg)

  • Shannon Smyly

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Ji-Chun Yang

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Sarah L. Maslen

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue
    The Francis Crick Institute)

  • Irmgard Sinning

    (Biochemiezentrum der Universität Heidelberg (BZH), INF328)

  • David Neuhaus

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Dean Clift

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

  • Leo C. James

    (MRC Laboratory of Molecular Biology, Francis Crick Avenue)

Abstract

TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn’t prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.

Suggested Citation

  • Leo Kiss & Tyler Rhinesmith & Jakub Luptak & Claire F. Dickson & Jonas Weidenhausen & Shannon Smyly & Ji-Chun Yang & Sarah L. Maslen & Irmgard Sinning & David Neuhaus & Dean Clift & Leo C. James, 2023. "Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37504-x
    DOI: 10.1038/s41467-023-37504-x
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    References listed on IDEAS

    as
    1. Leo Kiss & Dean Clift & Nadine Renner & David Neuhaus & Leo C. James, 2021. "RING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Frank Herkules & Corey H. Yu & Alexander B. Taylor & Vi Dougherty & Susan T. Weintraub & Dmitri N. Ivanov, 2022. "Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Hansjörg Götzke & Markus Kilisch & Markel Martínez-Carranza & Shama Sograte-Idrissi & Abirami Rajavel & Thomas Schlichthaerle & Niklas Engels & Ralf Jungmann & Pål Stenmark & Felipe Opazo & Steffen Fr, 2019. "The ALFA-tag is a highly versatile tool for nanobody-based bioscience applications," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Thomas Pertel & Stéphane Hausmann & Damien Morger & Sara Züger & Jessica Guerra & Josefina Lascano & Christian Reinhard & Federico A. Santoni & Pradeep D. Uchil & Laurence Chatel & Aurélie Bisiaux & M, 2011. "TRIM5 is an innate immune sensor for the retrovirus capsid lattice," Nature, Nature, vol. 472(7343), pages 361-365, April.
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    Cited by:

    1. Shanna S. Leventhal & Thomas Bisom & Dean Clift & Deepashri Rao & Kimberly Meade-White & Carl Shaia & Justin Murray & Evan A. Mihalakakos & Troy Hinkley & Steven J. Reynolds & Sonja M. Best & Jesse H., 2024. "Antibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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