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A protein quality control pathway regulated by linear ubiquitination
Author(s) -
Well Eva M,
Bader Verian,
Patra Maria,
SánchezVicente Ana,
Meschede Jens,
Furthmann Nikolas,
Schnack Cathrin,
Blusch Alina,
Longworth Joseph,
PetraschParwez Elisabeth,
Mori Kohji,
Arzberger Thomas,
Trümbach Dietrich,
Angersbach Lena,
Showkat Cathrin,
Sehr Dominik A,
Berlemann Lena A,
Goldmann Petra,
Clement Albrecht M,
Behl Christian,
Woerner Andreas C,
Saft Carsten,
Wurst Wolfgang,
Haass Christian,
Ellrichmann Gisa,
Gold Ralf,
Dittmar Gunnar,
Hipp Mark S,
Hartl F Ulrich,
Tatzelt Jörg,
Winklhofer Konstanze F
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100730
Subject(s) - huntingtin , proteotoxicity , biology , ubiquitin , microbiology and biotechnology , deubiquitinating enzyme , transcription factor , gene silencing , huntingtin protein , protein folding , biochemistry , gene , mutant
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.