Nature Communications (Dec 2023)
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. van 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,
- Konstanze F. Winklhofer
Affiliations
- Nikolas Furthmann
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Verian Bader
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Lena Angersbach
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Alina Blusch
- Department of Neurology, St Josef Hospital, Ruhr University Bochum
- Simran Goel
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Ana Sánchez-Vicente
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Laura J. Krause
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Sarah A. Chaban
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Prerna Grover
- Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Victoria A. Trinkaus
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry
- Eva M. van Well
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Maximilian Jaugstetter
- Analytical Chemistry II, Faculty of Chemistry and Biochemistry, Ruhr University Bochum
- Kristina Tschulik
- Cluster of Excellence RESOLV
- Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark
- Carsten Saft
- Department of Neurology, St Josef Hospital, Ruhr University Bochum
- Gisa Ellrichmann
- Department of Neurology, St Josef Hospital, Ruhr University Bochum
- Ralf Gold
- Department of Neurology, St Josef Hospital, Ruhr University Bochum
- Arend Koch
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology
- Benjamin Englert
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology
- Ana Westenberger
- Institute of Neurogenetics, University of Lübeck
- Christine Klein
- Institute of Neurogenetics, University of Lübeck
- Lisa Jungbluth
- Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich
- Carsten Sachse
- Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons (ER-C-3/Structural Biology), Forschungszentrum Jülich
- Christian Behrends
- Munich Cluster for Systems Neurology, Faculty of Medicine, Ludwig-Maximilians-Universität München
- Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf
- F. Ulrich Hartl
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry
- Ken Nakamura
- Gladstone Institute of Neurological Disease, Gladstone Institutes
- Chadwick W. Christine
- Department of Neurology, University of California
- Eric J. Huang
- Department of Neurology, University of California
- Jörg Tatzelt
- Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- Konstanze F. Winklhofer
- Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum
- DOI
- https://doi.org/10.1038/s41467-023-44033-0
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
