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

Autor: Furthmann N; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Bader V; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.; Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Angersbach L; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Blusch A; Department of Neurology, St Josef Hospital, Ruhr University Bochum, 44791, Bochum, Germany., Goel S; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Sánchez-Vicente A; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Krause LJ; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.; Cluster of Excellence RESOLV, 44801, Bochum, Germany., Chaban SA; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Grover P; Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Trinkaus VA; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany., van Well EM; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Jaugstetter M; Analytical Chemistry II, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Tschulik K; Cluster of Excellence RESOLV, 44801, Bochum, Germany.; Analytical Chemistry II, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, 44801, Bochum, Germany., Damgaard RB; Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800, Kongens Lyngby, Denmark., Saft C; Department of Neurology, St Josef Hospital, Ruhr University Bochum, 44791, Bochum, Germany., Ellrichmann G; Department of Neurology, St Josef Hospital, Ruhr University Bochum, 44791, Bochum, Germany.; Department of Neurology, Klinikum Dortmund, University Witten/Herdecke, 44135, Dortmund, Germany., Gold R; Department of Neurology, St Josef Hospital, Ruhr University Bochum, 44791, Bochum, Germany., Koch A; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, 10117, Berlin, Germany., Englert B; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, 10117, Berlin, Germany.; Center for Neuropathology and Prion Research, Ludwig-Maximilians University, 81377, Munich, Germany., Westenberger A; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Klein C; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Jungbluth L; Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich, Jülich, Germany.; Institute for Biological Information Processing (IBI-6/Cellular Structural Biology), Forschungszentrum Jülich, Jülich, Germany., Sachse C; Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich, Jülich, Germany.; Institute for Biological Information Processing (IBI-6/Cellular Structural Biology), Forschungszentrum Jülich, Jülich, Germany.; Department of Biology, Heinrich Heine University, Düsseldorf, Germany., Behrends C; Munich Cluster for Systems Neurology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany., Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251, Hamburg, Germany., Hartl FU; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany., Nakamura K; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, CA, USA., Christine CW; Department of Neurology, University of California, San Francisco, CA, USA.; Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Huang EJ; Department of Neurology, University of California, San Francisco, CA, USA.; Department of Pathology, University of California, San Francisco, CA, USA., Tatzelt J; Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.; Cluster of Excellence RESOLV, 44801, Bochum, Germany., Winklhofer KF; Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany. konstanze.winklhofer@rub.de.; Cluster of Excellence RESOLV, 44801, Bochum, Germany. konstanze.winklhofer@rub.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 19; Vol. 14 (1), pp. 8368. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1038/s41467-023-44033-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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