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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.* ; 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. ; Haass, C.* ; Ellrichmann, G.* ; Gold, R.* ; Dittmar, G.* ; Hipp, M.S.* ; Hartl, F.U.* ; Tatzelt, J.* ; Winklhofer, K.F.*

A protein quality control pathway regulated by linear ubiquitination.

EMBO J. 38:e100730 (2019)
Publ. Version/Full Text Preprint DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Huntingtin ; Lubac ; Otulin ; P97 ; Protein Aggregation
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 38, Issue: 8, Pages: , Article Number: e100730 Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)