Autophagy and the ubiquitin-proteasome system in cardiac dysfunction.

The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein degradation pathways. The UPS mediates the removal of soluble abnormal proteins as well as the targeted degradation of most normal proteins that are no longer needed. Autophagy is generally responsible for bulky removal of defective organelles and for sequestering portions of cytoplasm for lysosomal degradation during starvation. Impaired or inadequate protein degradation in the heart is associated with and may be a major pathogenic factor for a wide variety of cardiac dysfunctions, while enhanced protein degradation is also implicated in the development of cardiac pathology. It was generally assumed that the UPS and autophagy serve distinct functions. Therefore, the functional roles of the UPS and autophagy in the hearts have been largely investigated separately. However, recent advances in understanding the shared mechanisms contributing to UPS alteration and the induction of autophagy have helped reveal the link and interplay between the two proteolytic systems in the heart. These links are exemplified by scenarios in which inadequate UPS proteolytic function leads to activation of autophagy, helping alleviate proteotoxic stress. It is becoming increasingly clear that a coordinated and complementary relationship between the two systems is critical to protect cells against stress. Several proteins including p62, NBR1, HDAC6, and co-chaperones appear to play an important role in harmonizing and mobilizing the consortium formed by the UPS and autophagy.