期刊
EMBO JOURNAL
卷 38, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/embj.2018100730
关键词
Huntingtin; LUBAC; OTULIN; p97; protein aggregation
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [TA 167/6-1, WI 2111/4-1, WU 164/5-1, SFB1177]
- Munich Cluster for Systems Neurology
- Germany's Excellence Strategy-EXC-2033 [390677874]
- Hans and Ilse Breuer Foundation
- German Federal Ministry of Education and Research through the Integrated Network MitoPD and HIT-Tau [031A430E, 01EK1605C]
- Medical Faculty of the Ruhr University Bochum [FoRUM F832R-2014]
- German Research Foundation
- State Government of North Rhine-Westphalia [INST 213/840-1 FUGG]
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.
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