Journal Article

DZNE-2020-07029

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A protein quality control pathway regulated by linear ubiquitination.

van Well, E. M. ; Bader, V. ; Patra, M. ; Sánchez-Vicente, A. ; Meschede, J. ; Furthmann, N. ; Schnack, C. ; Blusch, A. ; Longworth, J. ; Petrasch-Parwez, E. ; Mori, K. ; Arzberger, T.DZNE* ; Trümbach, D. ; Angersbach, L. ; Showkat, C. ; Sehr, D. A. ; Berlemann, L. A. ; Goldmann, P. ; Clement, A. M. ; Behl, C. ; Woerner, A. C. ; Saft, C. ; Wurst, W.DZNE* ; Haass, C.DZNE* ; Ellrichmann, G. ; Gold, R. ; Dittmar, G. ; Hipp, M. S. ; Hartl, F. U. ; Tatzelt, J. ; Winklhofer, K. F. (Last author)DZNE*

2019
Wiley Hoboken, NJ [u.a.]

This record in other databases:    

Please use a persistent id in citations: doi:10.15252/embj.2018100730

Abstract: 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.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Animals (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Case-Control Studies (MeSH) ; Cells, Cultured (MeSH) ; Embryo, Mammalian: cytology (MeSH) ; Embryo, Mammalian: metabolism (MeSH) ; Female (MeSH) ; Fibroblasts: cytology (MeSH) ; Fibroblasts: metabolism (MeSH) ; Humans (MeSH) ; Huntingtin Protein: genetics (MeSH) ; Huntingtin Protein: metabolism (MeSH) ; Huntington Disease: genetics (MeSH) ; Huntington Disease: metabolism (MeSH) ; Huntington Disease: pathology (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Middle Aged (MeSH) ; NF-kappa B: genetics (MeSH) ; NF-kappa B: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Polyubiquitin: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Interaction Domains and Motifs (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Signal Transduction (MeSH) ; Sp1 Transcription Factor: genetics (MeSH) ; Sp1 Transcription Factor: metabolism (MeSH) ; Ubiquitination (MeSH) ; Valosin Containing Protein: genetics (MeSH) ; Valosin Containing Protein: metabolism (MeSH) ; HTT protein, human ; Huntingtin Protein ; NF-kappa B ; Sp1 Transcription Factor ; Sp1 protein, human ; Polyubiquitin ; Valosin Containing Protein

---

Contributing Institute(s):

1. Clinical Neurodegeneration (AG Levin)
2. Genome Engineering (AG Wurst)
3. Molecular Neurodegeneration (AG Haass)
4. Neurobiochemistry (AG Winklhofer)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
3. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2019

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

---