A protein quality control pathway regulated by linear ubiquitination

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.

Linear Ubiquitin Chains: Cellular Functions and Strategies for Detection and Quantification

“…LUBAC is not only recruited to cytosolic bacteria but also to cytosolic protein aggregates, suggesting that assemblies of misfolded proteins are sensed as a special kind of "cellular pathogen" or danger-associated molecular pattern (van Well et al, 2019). We observed that LUBAC modifies misfolded Huntingtin containing a pathogenic polyglutamine expansion (Htt-polyQ) with M1-linked ubiquitin and thereby shapes the ubiquitin coat of these aggregates.…”

“…chain assembly at Htt-polyQ aggregates, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, such as the sequestration of low complexity domaincontaining transcription factors that causes transcriptional dysregulation in Huntington's disease. Moreover, LUBAC facilitates proteasomal degradation of misfolded Htt-polyQ species in a p97/VCP-dependent manner (van Well et al, 2019).…”

Emerging Roles and Research Tools of Atypical Ubiquitination

“…In addition to the regulatory role of inflammation and cell death, linear polyubiquitination have recently been found to participate in controlling the clearance of misfolded proteins through NF‐κB‐independent pathways …”

Strategies to Investigate Ubiquitination in Huntington's Disease

“…TRAF6 expression also enhanced aggregate formation and atypical ubiquitination of mHtt aggregates (Zucchelli et al, 2011). Htt aggregates were shown to be modified with linear M1-linked polyubiquitin chains (van Well et al, 2019). Usually ubiquitin associates with its C-terminal glycine residue to a lysine residue on a target protein, but in M1-linked ubiquitination the protein's N-terminal methionine is the target for ubiquitination.…”