Proteins not only are the building blocks of the cell body but also execute nearly all the cellular functions. The long-term wellbeing of the cell is thus inextricably associated with protein quality control (PQC), which functions to minimize the production of abnormal proteins in the cell, remove unsalvageable abnormal proteins, and prevent abnormal proteins from damaging the cell. Abnormal proteins can arise from genetic mutations, errors in transcription, translation and folding, or damages resulting from environmental insults. When a misfolded or damaged protein fails to be repaired by chaperones-mediated processes, it will be degraded by targeted proteolysis.1
When PQC is impaired or overloaded, abnormal proteins accumulate and cause aberrant aggregation in the cell, thereby injuring the cell and ultimately leading to cell death. This can be quite detrimental to post-mitotic organs such as the heart and brain, due to their very limited, if any, self-renewal capacity.2
PQC depends on sophisticated collaboration between molecular chaperones and targeted proteolysis. The latter was previously believed to be carried out solely by the ubiquitin-proteasome system (UPS), but recent advances in this area of research suggest an important role for autophagy in PQC-associated proteolysis (Figure
Since the targeted proteolysis, especially that mediated by the UPS, is also responsible for the degradation of the majority of normal cellular proteins that are no longer needed, dysfunctional protein degradation will affect not only PQC but also many other cellular processes as reviewed by other articles in this Spotlight Issue
This review article focuses on the PQC perspective.
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 (more ...)
The importance of PQC in cell function and viability is demonstrated by overexpression of a molecular chaperone, and an ATP-dependent protease essential to mitochondrial PQC increased the healthy lifespan of Podospora anserine
Conversely, inhibitors of molecular chaperones and proteasomes have become promising new drug candidates for cancer chemotherapies.8,9
The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which is a family of cardiac disease caused by expression of aggregation-prone proteins in cardiomyocytes. Here, we will examine the current evidence, as it relates to the hypothesis that proteasome functional insufficiency (PFI) impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathy to congestive heart failure (CHF).