Build it up-Tear it down: protein quality control in the cardiac sarcomere

Abstract

The assembly and maintenance of the cardiac sarcomere, which contains the basic contractile components of actin and myosin, are essential for cardiac function. While often described as a static structure, the sarcomere is actually dynamic and undergoes constant turnover, allowing it to adapt to physiological changes while still maintaining function. A host of new factors have been identified that play a role in the regulation of protein quality control in the sarcomere, including chaperones that mediate the assembly of sarcomere components and ubiquitin ligases that control their specific degradation. There is clear evidence of sarcomere disorganization in animal models lacking muscle-specific chaperone proteins, illustrating the importance of these molecules in sarcomere structure and function. Although ubiquitin ligases have been found within the sarcomere structure itself, the role of the ubiquitin proteasome system in cardiac sarcomere regulation, and the factors that control its activity, are only just now being elucidated. The number of ubiquitin ligases identified with specificity for sarcomere proteins, each with distinct target substrates, is growing, allowing for tight regulation of this system. In this review, we highlight the dynamic interplay between sarcomere-specific chaperones and ubiquitin-dependent degradation of sarcomere proteins that is necessary in order to maintain structure and function of the cardiac sarcomere.

Figure 1

Sarcomere-specific chaperones and ubiquitin ligases are necessary for the assembly and degradation of sarcomere proteins and constitute the protein quality control system in the heart. The protein quality control of the sarcomere involves the continuous assembly (left side) and degradation (right side) of specific sarcomere proteins. In this example, the co-chaperones UNC-45 and Hsp90 are required for the assembly of myosin. This is balanced by the specific ubiquitination and degradation of proteins by the ubiquitin proteasome system. This involves specific ubiquitin ligases (designated E3) that place poly-ubiquitin tails on targets for degradation by the 26S proteasome. In this example, both MuRF1 and MuRF3 have shown to specifically ubiquitinate and degrade myosin in a proteasome-dependent manner. In the heart, this dynamic process of protein quality control occurs amid continuous use in order to maintain the fundamental construct necessary for contractility. Proteasome graphic courtesy of the U.S. Department of Energy Genome Programs (http://genomics.energy.gov).

Figure 2

Cardiac calpain-1 is necessary for cardiac proteins to be ubiquitinated. In order for sarcomere proteins to be ubiquitinated by ubiquitin ligases, calpain-1 activated release of the sarcomere appears necessary (left). Calpain-1 is also necessary for the regular turnover of aggregated proteins, which if not cleared, can result in increased autophagy. Adapted from Galvez et al.

Figure 3

Regulation of protein quality control by autophagy. The best defined regulator of autophagy to date is the target of rapamycin (TOR) kinase, which signals upstream of the Atg family of genes, which include more than 20 evolutionary conserved genes essential to autophagy. Target of rapamycin kinase is regulated by growth factor signalling, such as Akt signalling, thereby completing a nutrient-sensitive autophagy regulatory circuit. Other ‘sensing’ molecules contribute to autophagy activation, such as the energy sensor 5′-AMP-activated protein kinase (AMPK) and the nutrient-sensitive eukaryotic initiation factor 2alpha (eIF2alpha). Autophagy describes a multi-step process (nucleation, elongation, and completion) of a double-membrane vesicle forming around cytoplasmic cargo developing into an autophagosome. Subsequent docking and fusion of the autophagosome with a lysosome forms an autolysosome and exposes the cargo to lysosomal proteases leading to cargo degradation. Given the variety of stimuli that can activate autophagy, it is not surprising that multiple regulators of autophagy have been identified. For an exhaustive discussion of these and other regulatory proteins with a focus on disease pathogenesis, readers are encouraged to read excellent recent reviews on this topic.^, Inset: Inhibiting autophagy, in this case by knocking out cardiac Atg5 in mice, leads to prominent defects in the sarcomere structure, leading to sarcomere and mitochondrial disarray in the heart. Adapted from Levine and Kroemer.