LUBAC; OTULIN; Huntingtin; p97; protein aggregation; HTT protein, human; Huntingtin Protein; NF-kappa B; Sp1 Transcription Factor; SP1 protein, human; Polyubiquitin; Valosin Containing Protein; Adult; Aged; Animals; Brain/metabolism; Brain/pathology; Case-Control Studies; Cells, Cultured; Embryo, Mammalian/cytology; Embryo, Mammalian/metabolism; Female; Fibroblasts/cytology; Fibroblasts/metabolism; Humans; Huntingtin Protein/genetics; Huntingtin Protein/metabolism; Huntington Disease/genetics; Huntington Disease/metabolism; Huntington Disease/pathology; Male; Mice; Mice, Knockout; Middle Aged; NF-kappa B/genetics; NF-kappa B/metabolism; Neurons/metabolism; Neurons/pathology; Polyubiquitin/metabolism; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction; Sp1 Transcription Factor/genetics; Sp1 Transcription Factor/metabolism; Ubiquitination; Valosin Containing Protein/genetics; Valosin Containing Protein/metabolism; Protein Processing, Post-Translational; Brain; Embryo, Mammalian; Fibroblasts; Huntington Disease; Neurons; Neuroscience (all); Molecular Biology; Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Neuroscience
Abstract :
[en] Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
van Well, Eva M; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Bader, Verian ; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Patra, Maria; Neurobiochemistry, Adolf Butenandt Institute, Ludwig-Maximilians-University Munich, Munich, Germany
Sánchez-Vicente, Ana; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Meschede, Jens; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Furthmann, Nikolas; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Schnack, Cathrin; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Blusch, Alina; Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
LONGWORTH, Joseph ; Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
Petrasch-Parwez, Elisabeth; Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
Mori, Kohji ; Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany
Arzberger, Thomas; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany ; Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Trümbach, Dietrich; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Angersbach, Lena; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Showkat, Cathrin; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Sehr, Dominik A; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Berlemann, Lena A; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Goldmann, Petra; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
Clement, Albrecht M; Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
Behl, Christian; Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
Woerner, Andreas C; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany
Saft, Carsten; Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
Wurst, Wolfgang; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany ; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ; Developmental Genetics, Technical University Munich, Neuherberg, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Haass, Christian ; Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Ellrichmann, Gisa; Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
Gold, Ralf; Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
DITTMAR, Gunnar ; Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg
Hipp, Mark S ; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Hartl, F Ulrich ; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Tatzelt, Jörg ; Neurobiochemistry, Adolf Butenandt Institute, Ludwig-Maximilians-University Munich, Munich, Germany ; Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany ; Cluster of Excellence RESOLV, Bochum, Germany
Winklhofer, Konstanze F ; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany konstanze.winklhofer@rub.de ; Neurobiochemistry, Adolf Butenandt Institute, Ludwig-Maximilians-University Munich, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Cluster of Excellence RESOLV, Bochum, Germany
We thank Drs. A. Voigt for Htt-polyQ plasmids, H. Meyer for the p97/VCP plasmid, N. Mizushima for ATG5 KO MEFs, L. Lanier for providing videos of striatal neuron preparation, and Genentech for providing the 1F11/3F5/Y102L antibody. We wish to thank the patients and their families for brain samples. The research leading to these results has received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (TA 167/6-1, WI 2111/4-1, WU 164/5-1, SFB1177 to C.B.), the Munich Cluster for Systems Neurology (C.H., F.U.H., K.F.W., M.S.H., W.W.), Germany’s Excellence Strategy— EXC-2033—Projektnummer 390677874 (J.T., K.F.W.), the Hans and Ilse Breuer Foundation (M.P.), the German Federal Ministry of Education and Research through the Integrated Network MitoPD and HIT-Tau (grants 031A430E and 01EK1605C to W.W.), and the Medical Faculty of the Ruhr University Bochum (FoRUM F832R-2014 to K.F.W.). SR-SIM microscopy was funded by the German Research Foundation and the State Government of North Rhine-Westphalia (INST 213/840-1 FUGG).
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