Nikolas Furthmann, Verian Bader, Lena Angersbach, Alina Blusch, Simran Goel, Ana Sánchez-Vincente, Laura J. Krause, Sarah A. Chaban, Prerna Grover, Victoria A. Trinkaus, Eva Madeleine 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, Franz-Ulrich Hartl, Ken Nakamura, Chadwick W. Christine, Eric J. Huang, Jörg Tatzelt, Konstanze Winklhofer
- NEMO is a ubiquitin-binding protein which regulates canonical NF-\(\kappa\)B pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-\(\kappa\)B-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 \(\it IKBKG\) gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including \(\alpha\)-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at \(\alpha\)-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.
Metadaten| Author: | Nikolas FurthmannGND, Verian BaderORCiDGND, Lena AngersbachGND, Alina BluschGND, Simran GoelORCiDGND, Ana Sánchez-VincenteGND, Laura J. KrauseORCiDGND, Sarah A. ChabanORCiDGND, Prerna GroverORCiDGND, Victoria A. TrinkausGND, Eva Madeleine van WellGND, Maximilian JaugstetterGND, Kristina TschulikORCiDGND, Rune Busk DamgaardORCiDGND, Carsten SaftORCiDGND, Gisa EllrichmannORCiDGND, Ralf GoldORCiDGND, Arend KochGND, Benjamin EnglertORCiDGND, Ana WestenbergerGND, Christine KleinGND, Lisa JungbluthORCiDGND, Carsten SachseORCiDGND, Christian BehrendsORCiDGND, Markus GlatzelORCiDGND, Franz-Ulrich HartlORCiDGND, Ken NakamuraGND, Chadwick W. ChristineORCiDGND, Eric J. HuangORCiDGND, Jörg TatzeltORCiDGND, Konstanze WinklhoferORCiDGND |
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| URN: | urn:nbn:de:hbz:294-125423 |
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| DOI: | https://doi.org/10.1038/s41467-023-44033-0 |
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| Parent Title (English): | Nature communications |
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| Publisher: | Springer Nature |
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| Place of publication: | Berlin |
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| Document Type: | Article |
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| Language: | English |
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| Date of Publication (online): | 2024/04/12 |
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| Date of first Publication: | 2023/12/19 |
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| Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
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| Tag: | Open Access Fonds |
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| Volume: | 14 |
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| Issue: | Artikel 8368 |
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| First Page: | 8368-1 |
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| Last Page: | 8368-24 |
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| Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
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| Institutes/Facilities: | Institut für Biochemie und Pathobiochemie, Abteilung für Molekulare Zellbiologie |
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| Dewey Decimal Classification: | Naturwissenschaften und Mathematik / Chemie, Kristallographie, Mineralogie |
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| open_access (DINI-Set): | open_access |
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| faculties: | Fakultät für Chemie und Biochemie |
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| Licence (German): |  Creative Commons - CC BY 4.0 - Namensnennung 4.0 International |
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