Breaking Down the COP9 Signalsome in the Heart

Cellular function depends on protein homeostasis, also known as proteostasis.1 Proteostasis requires the efficient folding of nascent proteins, as well as the maintenance of mature protein folding. Overseeing proteostasis is a quality control process involving the surveillance of protein-folding status and the subsequent degradation of proteins that are not properly folded. Imbalanced proteostasis resulting from the accumulation of misfolded and unfolded proteins can lead to proteotoxicity, cell death, and ultimately organ failure. Many diseases, including neurodegenerative, hepatic, endocrine, and cardiovascular disorders, are thought to be associated with, if not caused by the organ failure resulting from impaired protein folding.2 For example, in the heart, impaired protein folding is associated with hypertrophic and dilated cardiomyopathies, as well as ischemic heart disease.3 Therefore, a better appreciation of the mechanisms governing the recognition and degradation of misfolded proteins will improve our understanding of cardiac physiology and pathology.Article, see p 956 Cells have evolved an elaborate protein quality control system that is designed to adjust the molecular machinery required to enhance protein-folding capacity and to degrade misfolded proteins via the ubiquitin proteasome system (UPS). If the UPS is sufficient to remove misfolded proteins, proteotoxicity can be averted; however, UPS insufficiency can result in proteotoxicity. Accordingly, the UPS aspect of protein quality control is essential for normal cell and organ function.4Most UPS-mediated protein degradation is an ATP-dependent process that involves ubiquitin-specific E1 activating, E2 conjugating, and E3 ubiquitin ligases, the latter of which functions in concert with chaperones to identify and ubiquitylate appropriate target proteins, such as misfolded proteins that contribute to impaired heart function (Figure). The resulting ubiquitylated proteins are then transferred to the proteasome, where they are degraded. The E3 ubiquitin ligases confer substrate specificity; therefore, they constitute the rate-limiting step of misfolded protein ubiquitylation.5 Because …