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
10 Reads
  • 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.
    Free Radical Biology and Medicine 03/2014; 71. DOI:10.1016/j.freeradbiomed.2014.03.031 · 5.74 Impact Factor
  • 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.
    American Journal of Cardiovascular Disease 01/2014; 4(4):140-58.
  • Source
    • "The cellular proteostasis machinery consists of molecular chaperones and of the cellular protein degradation machineries, such as the ubiquitin-proteasome system and autophagy pathways. Under optimal conditions, these mechanisms balance the cellular load of metastable and misfolded proteins [16], [17]. However, the expression of aggregation-prone proteins can interfere with the degradation of proteasome substrates, alter the subcellular distribution of essential proteins such as chaperones, and have deleterious effects on folding of other proteins [18], [19], [20], [21], [22]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid aggregates of the calcium-binding EF-hand proteins, S100A8 and S100A9, have been found in the corpora amylacea of patients with prostate cancer and may play a role in carcinogenesis. Here we present a novel model system using the yeast Saccharomyces cerevisiae to study human S100A8 and S100A9 aggregation and toxicity. We found that S100A8, S100A9 and S100A8/9 cotransfomants form SDS-resistant non-toxic aggregates in yeast cells. Using fluorescently tagged proteins, we showed that S100A8 and S100A9 accumulate in foci. After prolonged induction, S100A8 foci localized to the cell vacuole, whereas the S100A9 foci remained in the cytoplasm when present alone, but entered the vacuole in cotransformants. Biochemical analysis of the proteins indicated that S100A8 and S100A9 alone or coexpressed together form amyloid-like aggregates in yeast. Expression of S100A8 and S100A9 in wild type yeast did not affect cell viability, but these proteins were toxic when expressed on a background of unrelated metastable temperature-sensitive mutant proteins, Cdc53-1p, Cdc34-2p, Srp1-31p and Sec27-1p. This finding suggests that the expression and aggregation of S100A8 and S100A9 may limit the capacity of the cellular proteostasis machinery. To test this hypothesis, we screened a set of chaperone deletion mutants and found that reducing the levels of the heat-shock proteins Hsp104p and Hsp70p was sufficient to induce S100A8 and S100A9 toxicity. This result indicates that the chaperone activity of the Hsp104/Hsp70 bi-chaperone system in wild type cells is sufficient to reduce S100A8 and S100A9 amyloid toxicity and preserve cellular proteostasis. Expression of human S100A8 and S100A9 in yeast thus provides a novel model system for the study of the interaction of amyloid deposits with the proteostasis machinery.
    PLoS ONE 03/2013; 8(3):e58218. DOI:10.1371/journal.pone.0058218 · 3.23 Impact Factor
Show more