Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126, USA.
Circ Res. 2010 Feb 19;106(3):463-78. doi: 10.1161/CIRCRESAHA.109.208801.
The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.
泛素蛋白酶体系统（UPS）在心血管系统发育和心血管疾病相关的生物学过程中起着至关重要的作用。UPS 通常识别特定的蛋白质底物，并在其上放置多聚泛素链，以便随后被蛋白酶体破坏。该系统不仅降解错误折叠和受损的蛋白质，而且对于调节涉及增殖、适应应激、细胞大小调节和细胞死亡的多种细胞信号通路也是必不可少的。在心血管系统发育过程中，UPS 通过修饰转录因子、受体和结构蛋白来调节细胞信号。后来，在动脉粥样硬化、心肌肥厚和缺血/再灌注损伤等各种心血管疾病中，泛素连接酶和蛋白酶体都与保护和加重临床结局有关。然而，当 UPS 将错误折叠和受损的蛋白质泛素化时，由于它们的聚集构象，它们被蛋白酶体破坏并不总是可能的。最近的研究发现了 UPS 泛素化的错误折叠蛋白如何通过替代“特异性”机制被破坏。细胞质受体 p62、NBR 和组蛋白去乙酰化酶 6 识别聚集的泛素化蛋白，并将其靶向自噬，这一过程被称为“选择性自噬”。甚至整个细胞器内的多种蛋白质的泛素化也可能部分归因于类似的泛素驱动机制，从而驱动更普遍的巨自噬。总之，UPS 和自噬之间的串扰强调了 UPS 在维持蛋白质质量控制和调节心血管发育和疾病方面的关键和多样化作用。
