AUTHOR=Banasiak Katarzyna , Szulc Natalia A. , Pokrzywa Wojciech 

TITLE=The Dose-Dependent Pleiotropic Effects of the UBB+1 Ubiquitin Mutant

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.650730

DOI=10.3389/fmolb.2021.650730

ISSN=2296-889X

ABSTRACT=<p>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 <italic>via</italic> 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<sup>+1</sup>. 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<sup>+1</sup> concentration disrupts proteasome processivity, leading to increased aggregation of toxic proteins. On the other hand, a low level of UBB<sup>+1</sup> improves stress resistance and extends lifespan. Here we summarize recent findings regarding the impact of UBB<sup>+1</sup> on Ub signaling and neurodegeneration. We also review the molecular basis of how UBB<sup>+1</sup> affects UPS components as well as its dose-dependent switch between cytoprotective and cytotoxic roles.</p>