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

Abstract

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.

Figure 1

A schematic illustration of PQC in the cell. Chaperones facilitate the folding of nascent polypeptides and the unfolding/refolding of misfolded proteins, prevent the misfolded proteins from aggregating, and escort terminally misfolded proteins for degradation by the UPS. The UPS degrades both misfolded/damaged proteins and most unneeded native proteins in the cell. This process involves two steps: first, covalent attachment of ubiquitin to a target protein by a cascade of chemical reactions catalysed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3); and then the degradation of the target protein by the proteasome. The autophagy-lysosomal pathway participates in PQC by helping remove protein aggregates formed by the misfolded proteins that have escaped from the surveillance of chaperones and the UPS. Protein aggregates or defective organelles are first segregated by an isolated double membrane (phagophore) to form autophagosomes, which later fuse with lysosomes to form autophagolysosomes, where the segregated content is degraded by lysosomal hydrolases. p62/SQSTM1 and NBR1 (neighbour of BRCA1 gene 1) mediate the activation of autophagy by aggregated ubiquitinated proteins. The legend for symbols used is shown in the box at the lower left.

Figure 2

A diagram to depict the hypothesis that PFI contributes to cardiac dysfunction. Under stress conditions, the increased production of abnormal proteins overwhelms the UPS, and the resultant aberrant protein aggregation impairs proteasome proteolytic function, leading to PFI. PFI in turn accumulates misfolded proteins, thereby forming a vicious cycle between accumulation of misfolded proteins and PFI. PFI can induce cardiomyocyte dysfunction and/or cardiomyocyte death, and the dysfunctional cardiomyocytes produce more misfolded proteins, thereby forming a vicious cycle between cardiac dysfunction and PFI. Aberrant protein aggregation and/or PFI activate the autophagy-lysosome pathway, which may help relieve proteotoxic stress and attenuate PFI-induced cardiomyocyte dysfunction. The legend for the symbols is the same as in Figure 1.