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  A protein quality control pathway regulated by linear ubiquitination

van Well, E. M., Bader, V., Patra, M., Sanchez-Vicente, A., Meschede, J., Furthmann, N., et al. (2019). A protein quality control pathway regulated by linear ubiquitination. EMBO Journal, 38(9): e100730. doi:10.15252/embj.2018100730.

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 Creators:
van Well, Eva M.1, Author
Bader, Verian1, Author
Patra, Maria1, Author
Sanchez-Vicente, Ana1, Author
Meschede, Jens1, Author
Furthmann, Nikolas1, Author
Schnack, Cathrin1, Author
Blusch, Alina1, Author
Longworth, Joseph1, Author
Petrasch-Parwez, Elisabeth1, Author
Mori, Kohji1, Author
Arzberger, Thomas1, Author
Truembach, Dietrich1, Author
Angersbach, Lena1, Author
Showkat, Cathrin1, Author
Sehr, Dominik A.1, Author
Berlemann, Lena A.1, Author
Goldmann, Petra1, Author
Clement, Albrecht M.1, Author
Behl, Christian1, Author
Woerner, Andreas C.2, Author              Saft, Carsten1, AuthorWurst, Wolfgang1, AuthorHaass, Christian1, AuthorEllrichmann, Gisa1, AuthorGold, Ralf1, AuthorDittmar, Gunnar1, AuthorHipp, Mark S.2, Author              Hartl, F. Ulrich2, Author              Tatzelt, Joerg1, AuthorWinklhofer, Konstanze F.1, Author more..
Affiliations:
1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: INDUCED GENE ACTIVATION; MET1-LINKED UBIQUITIN; HUNTINGTONS-DISEASE; STRUCTURAL BASIS; IN-VITRO; CHAINS; STRESS; OTULIN; MODEL; LUBACBiochemistry & Molecular Biology; Cell Biology; Huntingtin; LUBAC; OTULIN; p97; protein aggregation;
 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.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published online
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000468399700003
DOI: 10.15252/embj.2018100730
 Degree: -

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Title: EMBO Journal
  Other : EMBO J.
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 38 (9) Sequence Number: e100730 Start / End Page: - Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061