NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62
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Published:2023-12-19
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Furthmann NikolasORCID, Bader VerianORCID, Angersbach Lena, Blusch Alina, Goel Simran, Sánchez-Vicente Ana, Krause Laura J.ORCID, Chaban Sarah A.ORCID, Grover PrernaORCID, Trinkaus Victoria A., van Well Eva M., Jaugstetter Maximilian, Tschulik KristinaORCID, Damgaard Rune BuskORCID, Saft Carsten, Ellrichmann Gisa, Gold Ralf, Koch Arend, Englert BenjaminORCID, Westenberger Ana, Klein Christine, Jungbluth LisaORCID, Sachse CarstenORCID, Behrends ChristianORCID, Glatzel MarkusORCID, Hartl F. UlrichORCID, Nakamura Ken, Christine Chadwick W.ORCID, Huang Eric J.ORCID, Tatzelt Jörg, Winklhofer Konstanze F.ORCID
Abstract
AbstractNEMO 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.
Funder
Deutsche Forschungsgemeinschaft Michael J. Fox Foundation for Parkinson's Research DH | NIHR | Health Services Research Programme
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference116 articles.
1. Kwon, Y. T. & Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 42, 873–886 (2017). 2. Johnston, H. E. & Samant, R. S. Alternative systems for misfolded protein clearance: life beyond the proteasome. FEBS J. 288, 4464–4487 (2021). 3. Le Guerroue, F. & Youle, R. J. Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective. Cell Death Differ. 28, 439–454 (2021). 4. Lei L., Wu Z., Winklhofer K. F. Protein quality control by the proteasome and autophagy: a regulatory role of ubiquitin and liquid-liquid phase separation. Matrix Biol. 100–101, 9–22 (2020). 5. Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).
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