Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50931, Germany and.
Genetics. 2020 Aug;215(4):889-901. doi: 10.1534/genetics.120.301283.
Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.
维持蛋白质组的健康是生物体每个细胞的终身挑战。然而，由于在源自不断变化的代谢、环境和病理条件的蛋白质毒性应激下，受损蛋白质不断积累，蛋白质的内稳性或蛋白质稳态经常受到威胁。蛋白质稳态是通过一个保守的质量控制途径网络来实现的，该网络协调正确折叠蛋白质的生物发生，防止蛋白质错误折叠，并通过选择性降解去除潜在有害的蛋白质。然而，蛋白质稳态网络的容量有限，其崩溃会降低细胞功能和生物体的存活能力，导致代谢、肿瘤或神经退行性疾病。虽然已经深入描述了细胞自主的质量控制机制，但最近对 的研究表明，蛋白质稳态在生物体的不同组织之间存在系统协调。这些发现表明存在错综复杂的平衡蛋白质稳态网络，这对于整合和维持生物体的蛋白质组至关重要，为定义蛋白质聚集疾病的新治疗靶点开辟了新的途径。在这里，我们概述了单个蛋白质质量控制途径以及中央蛋白质稳态节点之间的系统协调。我们进一步深入了解细胞和生物体蛋白质稳态机制的动态调节，这些机制整合了环境和代谢变化。使用 作为模型，开创了我们对保护生物体蛋白质组在健康和疾病中重要的保守质量控制机制的理解。
