Tearin' up my heart: proteolysis in the cardiac sarcomere

Abstract

Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system-mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere.

FIGURE 1.

The integrated proteolytic system in the heart. Upper, specific sarcomere proteins (indicated as substrates) are recognized by E3 enzymes (ubiquitin ligases) and ubiquitinated in a multistep process. This UPS involves an E1 enzyme that activates ubiquitin (Ub), which is transferred to one of many E2 enzymes. The E3 enzyme (ubiquitin ligase) gives specificity to the ubiquitination process by interacting with specific substrates and then catalyzing the transfer of the ubiquitin from E2 to the substrate in an ATP-dependent manner. Ubiquitinated substrates with canonical Lys-48 chains are then recognized by the 26 S proteasome and targeted for degradation. Access to sarcomere substrates by ubiquitin ligases (E3) may require the proteolytic action of calpains or caspases (indicated by the dashed arrow). Lower (adapted from Ref. 80), aggregated proteins unable to be degraded by the proteasome system, as well as proteins in complex such as those making up the actomyosin complex, may be targeted in a parallel lysosomal pathway by the process of autophagy. Ubiquitin labeling of proteins may also target proteins to the autophagosome for lysosomal degradation, assisting the UPS in clearing damaged or worn proteins. The LC3 conjugation system modifies proteins with PE, which is localized to the inner and outer membranes of autophagosomes. Inner membrane LC3-PE is degraded after lysosomes fuse with the autophagosomes. DUBS, deubiquitinating enzymes.