Autophagy and the ubiquitin-proteasome system in cardiac dysfunction

Abstract

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.

Figure 1. A summary of factors that impair the UPS and the potentially pathways that lead autophagy to participate in cellular processes

AMPK, AMP dependent kinase; ER, endoplasmic reticulum.

Figure 2. A schematic illustration of the interplay between the ubiquitin-proteasome system (UPS) and autophagy in removal of misfolded proteins

The UPS degrades soluble misfolded proteins. Aberrant protein aggregation impairs proteasome proteolytic function and insufficient proteasome function in turn further accumulates misfolded proteins, thereby forming a vicious cycle. The inadequate or impaired UPS might activate the autophagy-lysosome pathway as a compensatory mechanism. The autophagy-lysosome pathway removes both soluble oligomers of misfolded proteins and protein aggregates. p62 and NBR1 recognize ubiquitinated proteins and mediate their autophagic degradation. HDAC6 binds to ubiquitinated proteins and facilitates their transportation along microtubules toward the microtubule organizing center (MTOC), where ubiquitinated proteins are organized into aggresomes. Moreover, the autophagic degradation of aggresomes is promoted by HDAC6. As co-chaperones, BAG1 and BAG3 regulate proteasomal and autophagic pathways, respectively.