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

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, Maximilian Jaugstetter, Kristina Tschulik, Rune Busk Damgaard, Carsten Saft, Gisa Ellrichmann, Ralf Gold, Arend Koch, Benjamin Englert, Ana Westenberger, Christine Klein, Lisa Jungbluth, Carsten Sachse, Christian Behrends, Markus Glatzel, F. Ulrich Hartl, Ken Nakamura, Chadwick W. Christine, Eric J. Huang, Jörg Tatzelt and Konstanze F. Winklhofer ()
Additional contact information
Nikolas Furthmann: Ruhr University Bochum
Verian Bader: 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
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
Rune Busk Damgaard: Technical University of Denmark
Carsten Saft: Ruhr University Bochum
Gisa Ellrichmann: Ruhr University Bochum
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
Ana Westenberger: University of Lübeck
Christine Klein: University of Lübeck
Lisa Jungbluth: Forschungszentrum Jülich
Carsten Sachse: Forschungszentrum Jülich
Christian Behrends: Ludwig-Maximilians-Universität München
Markus Glatzel: University Medical Center Hamburg-Eppendorf
F. Ulrich Hartl: Max Planck Institute of Biochemistry
Ken Nakamura: Gladstone Institutes
Chadwick W. Christine: University of California
Eric J. Huang: University of California
Jörg Tatzelt: Ruhr University Bochum
Konstanze F. Winklhofer: Ruhr University Bochum

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44033-0

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DOI: 10.1038/s41467-023-44033-0

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