The Dose-Dependent Pleiotropic Effects of the UBB+1 Ubiquitin Mutant
Katarzyna Banasiak, Natalia A. Szulc, Wojciech Pokrzywa
Abstract
The proteolytic machinery activity diminishes with age, leading to abnormal accumulation of aberrant proteins; furthermore, a decline in protein degradation capacity is associated with multiple age-related proteinopathies. Cellular proteostasis can be maintained via the removal of ubiquitin (Ub)-tagged damaged and redundant proteins by the ubiquitin-proteasome system (UPS). However, during aging, central nervous system (CNS) cells begin to express a frameshift-mutated Ub, UBB +1 . Its accumulation is a neuropathological hallmark of tauopathy, including Alzheimer’s disease and polyglutamine diseases. Mechanistically, in cell-free and cell-based systems, an increase in the UBB +1 concentration disrupts proteasome processivity, leading to increased aggregation of toxic proteins. On the other hand, a low level of UBB +1 improves stress resistance and extends lifespan. Here we summarize recent findings regarding the impact of UBB +1 on Ub signaling and neurodegeneration. We also review the molecular basis of how UBB +1 affects UPS components as well as its dose-dependent switch between cytoprotective and cytotoxic roles.