Ubiquitin, an 8.6-kDa highly conserved protein, is a landmark molecule functioning as a posttranslational modifier. It is covalently attached to target proteins in a fashion of polymerization, resulting in a poly-ubiquitin chain that serves as a degradation signal. The 26S proteasome is an eukaryotic ATP-dependent protease responsible for selective degradation of the polyubiquitin-tagged proteins in eukaryotic cells. It appears to act as an elegantly organized apparatus designed for efficient and exhaustive hydrolysis of proteins, and can in fact be regarded as a protein-destroying machinery. To date, there are growing lines of evidence addressing the importance of the ubiquitin-proteasome system that catalyzes various biological reactions rapidly, orderly, exhaustively, and unidirectionally. On the other hand, autophagy (Greek for “self-eating”) is an evolutionarily conserved pathway in which the cytoplasm and organelles are engulfed within double-membraned vesicles, known as autophagosomes, which rapidly fuse with lysosomes and their contents together with the inner membrane are degraded by a variety of lysosomal digestive enzymes. While autophagy has been thought to contribute to bulk degradation non-selectively, but recent genetic analaysis with mice reveals that ablation of autophagy leads to accumulation of ubiquitin-positive inclusions, implying that the novel role of ubiquitin is to provide a signal that shuttles ubiquitinated proteins for autophagy. Currently, the roles of ubiqutin are expanding in various fields of life science. In this review, I will review the ubiquitin-mediated proteolysis pathway with a special reference to proteasomes and autophagy, focusing on how ubiquitin is linked to the pathogenesis of neurodegenerative diseases.
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