TY  - JOUR
AU  - van Well, Eva M
AU  - Bader, Verian
AU  - Patra, Maria
AU  - Sánchez-Vicente, Ana
AU  - Meschede, Jens
AU  - Furthmann, Nikolas
AU  - Schnack, Cathrin
AU  - Blusch, Alina
AU  - Longworth, Joseph
AU  - Petrasch-Parwez, Elisabeth
AU  - Mori, Kohji
AU  - Arzberger, Thomas
AU  - Trümbach, Dietrich
AU  - Angersbach, Lena
AU  - Showkat, Cathrin
AU  - Sehr, Dominik A
AU  - Berlemann, Lena A
AU  - Goldmann, Petra
AU  - Clement, Albrecht M
AU  - Behl, Christian
AU  - Woerner, Andreas C
AU  - Saft, Carsten
AU  - Wurst, Wolfgang
AU  - Haass, Christian
AU  - Ellrichmann, Gisa
AU  - Gold, Ralf
AU  - Dittmar, Gunnar
AU  - Hipp, Mark S
AU  - Hartl, F Ulrich
AU  - Tatzelt, Jörg
AU  - Winklhofer, Konstanze F
TI  - A protein quality control pathway regulated by linear ubiquitination.
JO  - The EMBO journal
VL  - 38
IS  - 9
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-07029
SP  - e100730
PY  - 2019
AB  - 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.
KW  - Adult
KW  - Aged
KW  - Animals
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Case-Control Studies
KW  - Cells, Cultured
KW  - Embryo, Mammalian: cytology
KW  - Embryo, Mammalian: metabolism
KW  - Female
KW  - Fibroblasts: cytology
KW  - Fibroblasts: metabolism
KW  - Humans
KW  - Huntingtin Protein: genetics
KW  - Huntingtin Protein: metabolism
KW  - Huntington Disease: genetics
KW  - Huntington Disease: metabolism
KW  - Huntington Disease: pathology
KW  - Male
KW  - Mice
KW  - Mice, Knockout
KW  - Middle Aged
KW  - NF-kappa B: genetics
KW  - NF-kappa B: metabolism
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Polyubiquitin: metabolism
KW  - Protein Binding
KW  - Protein Interaction Domains and Motifs
KW  - Protein Processing, Post-Translational
KW  - Signal Transduction
KW  - Sp1 Transcription Factor: genetics
KW  - Sp1 Transcription Factor: metabolism
KW  - Ubiquitination
KW  - Valosin Containing Protein: genetics
KW  - Valosin Containing Protein: metabolism
KW  - HTT protein, human (NLM Chemicals)
KW  - Huntingtin Protein (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Sp1 Transcription Factor (NLM Chemicals)
KW  - Sp1 protein, human (NLM Chemicals)
KW  - Polyubiquitin (NLM Chemicals)
KW  - Valosin Containing Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30886048
C2  - pmc:PMC6484417
DO  - DOI:10.15252/embj.2018100730
UR  - https://pub.dzne.de/record/140707
ER  -