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NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62

Author

Listed:
  • Nikolas Furthmann

    (Ruhr University Bochum)

  • Verian Bader

    (Ruhr University Bochum
    Ruhr University Bochum)

  • Lena Angersbach

    (Ruhr University Bochum)

  • Alina Blusch

    (Ruhr University Bochum)

  • Simran Goel

    (Ruhr University Bochum)

  • Ana Sánchez-Vicente

    (Ruhr University Bochum)

  • Laura J. Krause

    (Ruhr University Bochum
    Cluster of Excellence RESOLV)

  • Sarah A. Chaban

    (Ruhr University Bochum)

  • Prerna Grover

    (Ruhr University Bochum)

  • Victoria A. Trinkaus

    (Max Planck Institute of Biochemistry)

  • Eva M. Well

    (Ruhr University Bochum)

  • Maximilian Jaugstetter

    (Ruhr University Bochum)

  • Kristina Tschulik

    (Cluster of Excellence RESOLV
    Ruhr University Bochum)

  • Rune Busk Damgaard

    (Technical University of Denmark)

  • Carsten Saft

    (Ruhr University Bochum)

  • Gisa Ellrichmann

    (Ruhr University Bochum
    Klinikum Dortmund, University Witten/Herdecke)

  • Ralf Gold

    (Ruhr University Bochum)

  • Arend Koch

    (Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology)

  • Benjamin Englert

    (Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology
    Ludwig-Maximilians University)

  • Ana Westenberger

    (University of Lübeck)

  • Christine Klein

    (University of Lübeck)

  • Lisa Jungbluth

    (Forschungszentrum Jülich
    Forschungszentrum Jülich)

  • Carsten Sachse

    (Forschungszentrum Jülich
    Forschungszentrum Jülich
    Heinrich Heine University)

  • Christian Behrends

    (Ludwig-Maximilians-Universität München)

  • Markus Glatzel

    (University Medical Center Hamburg-Eppendorf)

  • F. Ulrich Hartl

    (Max Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy))

  • Ken Nakamura

    (Gladstone Institutes
    University of California)

  • Chadwick W. Christine

    (University of California
    University of California San Francisco)

  • Eric J. Huang

    (University of California
    University of California)

  • Jörg Tatzelt

    (Ruhr University Bochum
    Cluster of Excellence RESOLV)

  • Konstanze F. Winklhofer

    (Ruhr University Bochum
    Cluster of Excellence RESOLV)

Abstract

NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

Suggested Citation

  • Nikolas Furthmann & Verian Bader & Lena Angersbach & Alina Blusch & Simran Goel & Ana Sánchez-Vicente & Laura J. Krause & Sarah A. Chaban & Prerna Grover & Victoria A. Trinkaus & Eva M. Well & Maximil, 2023. "NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44033-0
    DOI: 10.1038/s41467-023-44033-0
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    References listed on IDEAS

    as
    1. Radu Tusco & Anne-Claire Jacomin & Ashish Jain & Bridget S. Penman & Kenneth Bowitz Larsen & Terje Johansen & Ioannis P. Nezis, 2017. "Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    2. Shun Kageyama & Sigurdur Runar Gudmundsson & Yu-Shin Sou & Yoshinobu Ichimura & Naoki Tamura & Saiko Kazuno & Takashi Ueno & Yoshiki Miura & Daisuke Noshiro & Manabu Abe & Tsunehiro Mizushima & Nobuak, 2021. "p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Elsje G. Otten & Emma Werner & Ana Crespillo-Casado & Keith B. Boyle & Vimisha Dharamdasani & Claudio Pathe & Balaji Santhanam & Felix Randow, 2021. "Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection," Nature, Nature, vol. 594(7861), pages 111-116, June.
    4. Shuang-zhou Peng & Xiao-hui Chen & Si-jie Chen & Jie Zhang & Chuan-ying Wang & Wei-rong Liu & Duo Zhang & Ying Su & Xiao-kun Zhang, 2021. "Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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