Kim Jiseong, Zhao Yuping, Kim Hyun Young, Kim Sumin, Jiang Yanxialei, Lee Min Jae
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
J Extracell Vesicles. 2025 May;14(5):e70086. doi: 10.1002/jev2.70086.
The 26S proteasome holoenzyme comprises 20S catalytic and 19S regulatory complexes. Accumulating evidence suggests that the majority of proteasomes in the extracellular space exist as free 20S proteasomes; however, their origin and pathophysiological function remain to be determined. Here, we report that cellular proteasomes are effectively packaged into the lumen of extracellular vesicles (EVs) and secreted in a structurally intact and enzymatically active 20S form. We further demonstrate that EV-encapsulated 20S proteasomes are delivered to recipient cells and facilitate the degradation of overexpressed tau proteins without disrupting global proteolytic pathways. These findings highlight a novel cell-to-cell communication system that transports the proteasomes to target cells for the clearance of proteotoxic substrates. Further characterisation of this homeostatic mechanism will improve our understanding of organismal stress response mechanisms and may provide a therapeutic approach to treat various proteinopathies, including Alzheimer's disease.
26S蛋白酶体全酶由20S催化复合物和19S调节复合物组成。越来越多的证据表明，细胞外空间中的大多数蛋白酶体以游离的20S蛋白酶体形式存在；然而，它们的来源和病理生理功能仍有待确定。在这里，我们报告细胞蛋白酶体被有效地包装到细胞外囊泡（EVs）的腔内，并以结构完整且具有酶活性的20S形式分泌。我们进一步证明，EV包裹的20S蛋白酶体被递送至受体细胞，并在不破坏整体蛋白水解途径的情况下促进过表达的tau蛋白的降解。这些发现突出了一种新型的细胞间通讯系统，该系统将蛋白酶体运输到靶细胞以清除蛋白毒性底物。对这种稳态机制的进一步表征将增进我们对机体应激反应机制的理解，并可能提供一种治疗包括阿尔茨海默病在内的各种蛋白病的治疗方法。
