Review of cardiac protein quality control and major degradation pathways

Protein quality control (PQC) senses and repairs misfolded and or unfolded proteins. However, if the repair fails, it degrades the terminally misfolded polypeptides through an intricate collaboration between molecular chaperones and targeted proteolysis. Proteolysis of damaged proteins is performed primarily by the ubiquitin-proteasome system (UPS). Macroautophagy (commonly known as autophagy) may also play a role in PQC-associated proteolysis, especially when UPS function becomes ineffective. The development of a range of heart diseases, including bona fide cardiac proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI). Proteasome functional insufficiency and activation of autophagy have been observed in the heart of mouse models of cardiac proteinopathy. Recent studies demonstrated that pharmacologically induced proteasome inhibition is sufficient to activate autophagy in cardiomyocytes in both intact animals and cell cultures. This had unveiled a potential cross-talk between the two major degradation pathways in cardiac PQC.