A role of linear ubiquitination in integrating immune and neuroprotective signaling

Identification: Winklhofer, Konstanze


A role of linear ubiquitination in integrating immune and neuroprotective signaling
Eva M. van Well1, Verian Bader1, Jens Meschede1, Ana Sánchez-Vicente1, Maria Patra2, Cathrin Schnack1, Alina Blusch1, Elisabeth Petrasch-Parwez1, Kohji Mori2, Thomas Arzberger2, Dietrich Trümbach3, Dominik A. Sehr1, Carsten Saft1, Wolfgang Wurst3, Christian Haass2, Ralf Gold1, Gisa Ellrichmann1, Mark S. Hipp4, F. Ulrich Hartl4, Jörg Tatzelt1, and Konstanze F. Winklhofer1*
1Ruhr University Bochum, Germany, 2Ludwig Maximilians University Munich, Germany, 3Helmholtz Zentrum München, Germany, 4Max Planck Institute of Biochemistry, Martinsried, Germany
*Corresponding Author
Linear ubiquitination is mediated by the linear ubiquitin chain assembly complex (LUBAC). HOIP is the catalytically active component of the LUBAC and the only known E3 ubiquitin ligase capable of assembling linear polyubiquitin. So far, LUBAC has been studied in the context of inflammation, immunity and defense pathways against intracellular pathogens where it is required for NF-κB activation. We tested a possible impact of LUBAC on protein aggregates linked to neurodegenerative diseases, which may be viewed as a special kind of "cellular pathogens". Employing various models of Huntington's disease (HD), including cellular and mouse models and human HD brain, we showed that LUBAC ubiquitinates Huntingtin aggregates, thereby remodeling their interactive surface and markedly decreasing aggregate toxicity. Our study provides the first evidence for an NF-κB-independent function of LUBAC and identifies linear ubiquitination as a novel target for disease-modifying strategies in protein aggregation diseases.


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