Sedlacek Jindrich
Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Pru°myslová 595, Vestec 252 50, Czech Republic.
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 16610 Prague, Czech Republic.
ACS Pharmacol Transl Sci. 2024 Dec 16;8(1):21-35. doi: 10.1021/acsptsci.4c00408. eCollection 2025 Jan 10.
The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.
26S蛋白酶体降解大多数细胞蛋白，并影响细胞生命的各个方面。因此，在不同的生命环境中，26S蛋白酶体的丰度、正确组装和活性需要得到精确控制。蛋白酶体活性受损被认为是几种严重疾病的致病因素。蛋白酶体生物学的最新进展表明，蛋白酶体可以被不同的因子或小分子激活。因此，激活的泛素依赖性蛋白酶体降解具有多种作用，如在不同模型中延长寿命、防止蛋白质聚集体的积累以及减少它们对细胞的负面影响。26S蛋白酶体介导的降解增加可减轻蛋白毒性应激，并有可能提高工程化降解剂（如PROTACs）的功效，特别是在蛋白酶体功能异常的情况下。本文总结了在转录和翻译后水平上对蛋白酶体进行药理学激活的新观点和最新见解。
