Cardiac muscle ring finger-1--friend or foe?

Abstract

The ubiquitin proteasome system plays a role in regulating protein activity and is integral to the turnover of damaged and worn proteins. In this review, we discuss the recently described relationship between the ubiquitin proteasome system and the cardiac creatine kinase/phosphocreatine shuttle, an essential component of adenosine triphosphate generation and energy shuttling within the heart. The ubiquitin ligase muscle ring finger-1 (MuRF1) binds creatine kinase, leading to its ubiquitination and possible degradation. Muscle ring finger-1 may also be integral in the regulation of creatine kinase activity in vivo. Because there is a close relationship between the cardiac creatine kinase/phosphocreatine shuttle activity and heart failure, these findings suggest that MuRF1's role in protein quality control of creatine kinase may be vital to the regulation and maintenance of cardiac energetics to protect against heart failure.

Figure 1

The canonical Ubiquitin Proteasome System (UPS). Protein ubiquitination is driven by the action of 3 successive enzymes. The ubiquitin-activating enzyme (E1) activates ubiquitin in an ATP-dependent manner, adding the ubiquitin to the subsequent ubiquitin conjugating (E2) enzyme. Ubiquitin is then transferred from the ubiquitin-charged E2 to the substrate and/or the growing ubiquitin chain by the activity of a ubiquitin ligase (E3), which gives the system specificity. The multi-ubiquitin chain attached to the substrate is recognized by the 26S proteasome, which degrades the substrate and ubiquitin chain. The selective nature of the ubiquitin ligases is the focus of many investigations since it drives the specificity of the reaction. The canonical UPS degradation system shown here represents a skeletal schematic for a much more complex system, with ancillary factors participating in substrate recognition and a pathway involved in regulating protein activities by post-translational modifications that don’t always lead to degradation (Elsasser et al. 2004;Li et al. 2007;Richly et al. 2005).

Figure 2

MuRF1’s regulation of CK activity in the heart and its effects on energy transfer. A. ATP (Energy) production. The metabolism of fatty acid and glucose leads to the production of ATP in the mitochondria via oxidative phosphorylation. B. ATP/Energy transfer by the Phospho-Creatine (PCr) Shuttle. The PCr shuttle transfers ATP by transferring high energy phosphates on to and off of creatine through the CK isoforms mtCK and CK-M/B. CK isoforms can be compartmentalized at specific intracellular sites or can be found free in the cytosol. The CK-MM isoform has been identified in myofibrils as part of the structures localized to the M band (Wallimann and Eppenberger 1985). C. ATP utilization by ATPases. CK-M/B localized adjacent to ATPases utilize ATP to perform work, such as sarcomere/muscle contraction, electromechanical coupling, and action potentials. The CK-MM is functionally coupled to the myosin ATPase, allowing the efficient maintenance of high ATP/ADP locally, stimulating ATPase activity and ensuring proper contraction of the muscle (Ventura-Clapier et al. 1994). CK-MM is also bound to the membranes of the sarcoplasmic reticulum, where it is coupled functionally to Ca²⁺-ATPase (Minajeva et al. 1996;Rossi et al. 1990), ensuring efficient energy provision of local generation of ATP. A smaller amount of CK-MM is associated with Na+/K+-ATPase (Wallimann et al. 1989). D. The ubiquitin proteasome system (UPS) in protein quality control. The UPS, including E1, E2, and E3’s such as MuRF1, interact and ubiquitinate CK, likely targeting the substrates for degradation in a dynamic process of protein quality control. Adapted from: Zhou 2005 (Zhao et al. 2007) and Willis (Willis and Patterson 2006).