The ubiquitin-proteasome system in cardiac proteinopathy: A quality control perspective

Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Lee Medical Building, 414 E Clark Street, Vermillion, SD 57069, USA.
Cardiovascular Research (Impact Factor: 5.94). 09/2009; 85(2):253-62. DOI: 10.1093/cvr/cvp287
Source: PubMed


Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure.

Download full-text


Available from: Xuejun Wang, Jun 03, 2015
    • "When this system is functionally compromised or overstrained, ubiquitinated protein accumulate in the cell. This pathophysiological process, termed proteasomal functional insufficiency (PFI), has been shown to be an important factor in the pathogenesis of desmin-related cardiomyopathies[44]and other cardiac muscle diseases[45]. In turn, stimulation of proteasome activity can be used to attenuate the phenotype of DRC[25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intercalated disc (ID) is a major component of the cell-cell contact structures of cardiomyocytes and has been recognized as a hot spot for cardiomyopathy. We have previously identified Myozap as a novel cardiac-enriched ID protein, which interacts with several other ID proteins and is involved in RhoA/SRF-signaling in vitro. To now study its potential role in vivo we generated a mouse model with cardiac overexpression of Myozap. Transgenic (Tg) mice developed cardiomyopathy with hypertrophy and LV dilation. Consistently, these mice displayed upregulation of the hypertrophy-associated and SRF-dependent gene expression. Pressure overload (transverse aortic constriction, TAC) caused exaggerated cardiac hypertrophy, further loss of contractility and LV dilation. Similarly, a physiological stimulus (voluntary running) also led to significant LV dysfunction. On the ultrastructural level, Myozap-Tg mouse hearts exhibited massive protein aggregates composed of Myozap, desmoplakin and other ID proteins. This aggregate-associated pathology closely resembled the alterations observed in desmin-related cardiomyopathy. Interestingly, desmin was not detectable in the aggregates, yet was largely displaced from the ID. Molecular analyses revealed induction of autophagy and dysregulation of the unfolded protein response (UPR), associated with apoptosis. Taken together, cardiac overexpression of Myozap leads to cardiomyopathy, mediated, at least in part by induction of Rho-dependent SRF signaling in vivo. Surprisingly, this phenotype was also accompanied by protein aggregates in cardiomyocytes, UPR alteration, accelerated autophagy and apoptosis. Thus, this mouse model may also offer additional insight into the pathogenesis of protein aggregate-associated cardiomyopathies and represents a new candidate gene itself.
    No preview · Article · Jul 2014 · Journal of Molecular and Cellular Cardiology
  • Source
    • "Proteinopathies are diseases that are characterized by protein misfolding and aggregation, including desmin-related cardiomyopathy (DRC) [280] [281]. Proteasome function insufficiency is observed in a variety of heart diseases [282] [283] in animals, i.e. myocardial ischemia/ reperfusion (I/R) injury and pressure overload-induced cardiomyopathy [281] [284] [285], as well as in humans, i.e. hypertrophic or dilated cardiomyopathy [283] [286]. Cardiomyocyte-restricted overexpression of the proteasome 28 subunit α (CR-PA28αOE) in mice caused augmentation of cardiac UPS proteolytic function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is a natural biological process that is characterized by a progressive accumulation of macromolecular damage. In the proteome, aging is accompanied by decreased protein homeostasis and function of the major cellular proteolytic systems, leading to the accumulation of unfolded, misfolded or aggregated proteins. In particular, the proteasome is responsible for the removal of normal as well as damaged or misfolded proteins. Extensive work during last several years has clearly demonstrated that proteasome activation by either genetic means or use of compounds significantly retards aging. Importantly, this represents a common feature across evolution thereby suggesting proteasome activation to be an evolutionary conserved mechanism of aging and longevity regulation. This review article reports on the means of function of these proteasome activators and how they regulate aging in different species.
    Full-text · Article · Mar 2014 · Free Radical Biology and Medicine
  • Source
    • "Insufficient proteasomal proteolysis is being recognized as an important pathogenic factor to various forms of cardiac disease [110] [111]. Although CSN has been long viewed as a UPS regulator due to its ability to control CRL activity and its structural similarity to the 19S proteasome lid [112], the in vivo experimental evidence is still lacking. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neddylation is a post-translational protein modification that conjugates a ubiquitin-like protein NEDD8 to target proteins. Similar to ubiquitination, neddylation is mediated by a cascade of three NEDD8 specific enzymes, an E1 activating enzyme, an E2 conjugating enzyme and one of the several E3 ligases. Neddylation is countered by the action of deneddylases via a process termed deneddylation. By altering the substrate's conformation, stability, subcellular localization or binding affinity to DNA or proteins, neddylation regulates diverse cellular processes including the ubiquitin-proteasome system-mediated protein degradation, protein transcription, cell signaling etc. Dysregulation of neddylation has been linked to cancer, neurodegenerative disorders, and more recently, cardiac disease. Here we comprehensively overview the biochemistry, the proteome and the biological function of neddylation. We also summarize the recent progress in revealing the physiological and pathological role of neddylation and deneddylation in the heart.
    Full-text · Article · Jan 2014 · American Journal of Cardiovascular Disease
Show more