A protein quality control pathway regulated by linear ubiquitination

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. Synopsis Misfolded proteins recruit the linear ubiquitin chain assembly complex (LUBAC) via p97/VCP, resulting in the assembly of linear ubiquitin chains at protein aggregates, such as Huntingtin with an polyQ expansion (Htt‐polyQ). This modification interferes with proteotoxicity of Htt‐polyQ by preventing sequestration of the transcription factor Sp1 and by promoting proteasomal degradation of misfolded Htt‐polyQ. The linear ubiquitin chain assembly complex (LUBAC) is recruited to misfolded protein species, such as mutant Huntingtin, Ataxin‐3, SOD1, and TDP‐43. Linear ubiquitination of mutant Huntingtin causes remodeling of its interactive surface. Expression of LUBAC is dysregulated in Huntington's disease by sequestration of the transcription factor Sp1 to misfolded Huntingtin. Linear ubiquitination promotes removal of misfolded protein species in a p97/VCP‐ and proteasome‐dependent manner. Graphical Abstract Recruitment of the LUBAC E3 ligase, best known for its function in NF‐κB signalling, to protein aggregates for linear ubiquitin‐mediated removal of misfolded neurodegenerative disease proteins such as huntingtin, SOD1 or TDP‐43 exempli