ABSTRACT This review focuses on recent advances in our understanding of the ubiquitin-proteasome-dependent pathway, which plays a major role in skeletal muscle proteolysis and is involved in the control of many major biological functions. The ubiquitination/deubiquitination system is a complex machine responsible for the specific tagging and proofreading of substrates degraded by the 26S proteasome, but ubiquitination itself also serves other functions. The formation of a polyubiquitin degradation signal is usually required for proteasome-dependent proteolysis. Hierarchical families of enzymes, which may comprise dozens of members to achieve high selectivity, control this process. The substrates tagged by ubiquitin are then recognized by the 26S proteasome and degraded into peptides. However, the 26S proteasome also recognizes and degrades some non-ubiquitinated proteins, and several proteasome populations participate in protein breakdown. Thus, mammalian cells contain multiple ubiquitin- and(or) proteasome-dependent pathways. These systems can degrade single proteins by alternative mechanisms and may also interfere or cooperate with other proteolytic pathways.
Implications
The precise mechanisms that regulate the ubiquitin-proteasome-dependent breakdown of some key proteins (e.g., cyclins, transcription factors) have started to be elucidated. In contrast, how this proteolytic pathway degrades muscle proteins, and more particularly contractile proteins, remains largely unknown. Information on the E2 and E3 that operate in muscle is still scarce. Similarly, neither the signals that target myofibrillar proteins for breakdown nor the precise substrates of the pathway have been identified. Studies that aim to explore the role of deubiquitinating enzyme and the regulation of proteolytic/peptidase activities of muscle proteasomes are also needed. Finally, the possible relationships of the ubiquitin-proteasome-pathway with the cathepsins and calpains should also be explored in depth. However, the complexity of the ubiquitin pathway will clearly impede the identification of the precise mechanisms that are important in the control of muscle proteolysis.
Key Words: Proteolysis, Ubiquitin, Proteinases, Calpains, Cathepsins, Skeletal Muscle
Ö2002 American Society of Animal Science. All rights reserved.
J. Anim. Sci. 80(E. Suppl. 2):E56-E63
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