Banasiak Katarzyna, Szulc Natalia A, Pokrzywa Wojciech
Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Front Mol Biosci. 2021 Mar 26;8:650730. doi: 10.3389/fmolb.2021.650730. eCollection 2021.
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 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. 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 concentration disrupts proteasome processivity, leading to increased aggregation of toxic proteins. On the other hand, a low level of UBB improves stress resistance and extends lifespan. Here we summarize recent findings regarding the impact of UBB on Ub signaling and neurodegeneration. We also review the molecular basis of how UBB affects UPS components as well as its dose-dependent switch between cytoprotective and cytotoxic roles.
蛋白水解机制的活性随年龄增长而降低，导致异常蛋白质的异常积累；此外，蛋白质降解能力的下降与多种与年龄相关的蛋白质病有关。细胞蛋白稳态可以通过泛素-蛋白酶体系统（UPS）清除泛素（Ub）标记的受损和冗余蛋白质来维持。然而，在衰老过程中，中枢神经系统（CNS）细胞开始表达移码突变的Ub，即UBB。其积累是包括阿尔茨海默病和多聚谷氨酰胺疾病在内的tau蛋白病的神经病理学标志。从机制上讲，在无细胞和基于细胞的系统中，UBB浓度的增加会破坏蛋白酶体的持续加工能力，导致有毒蛋白质的聚集增加。另一方面，低水平的UBB可提高抗应激能力并延长寿命。在这里，我们总结了关于UBB对Ub信号传导和神经退行性变影响的最新发现。我们还回顾了UBB如何影响UPS组件的分子基础，以及其在细胞保护和细胞毒性作用之间的剂量依赖性转换。
