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. 2008 Jan;4(1):65-75.
doi: 10.2217/14796678.4.1.65.

Appetite for destruction: E3 ubiquitin-ligase protection in cardiac disease

Monte S Willis  1 , Jonathan C Schisler, Cam Patterson
Affiliations

Appetite for destruction: E3 ubiquitin-ligase protection in cardiac disease

Monte S Willis et al. Future Cardiol. 2008 Jan.

Abstract

Over the course of 3 billion heartbeats in an average human lifetime, the heart must maintain constant protein quality control, including the coordinated and regulated degradation of proteins via the ubiquitin-proteasome system (UPS). Recent data highlight the specificity by which the UPS functions in the context of cardiac hypertrophy, ischemic heart disease and cardiomyopathies. Although curbing the appetite of the proteasome through the use of inhibitors in animal models of cardiac disease has proven effective experimentally, recent studies report proteasome inhibition as being cardiotoxic in some patients. Therefore, focusing on specific regulatory components of the proteasome, such as members of the E3 ubiquitin-ligase family of proteins, may hold promise for targeted therapeutics of cardiac disease. This review focuses on the UPS, its specific role in cardiac disease and opportunities for novel therapies.

Keywords: CHIP; MDM2; MuRF1; Velcade™; atrogin-1; bortezomib; cardiac; hypertrophy; ischemia; reperfusion.

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Figures

Figure 1
Figure 1. Overview of the ubiquitin-proteasome system
The degradation of proteins via the ubiquitin-proteasome system is dependent on the sequential addition of ubiquitin molecules on targeted protein substrates. (A) Free ubiquitin is activated by the E1 enzyme and transferred to an E2 enzyme. E3 ubiquitin ligases mediate the transfer of the ubiquitin molecule from the E2 to the substrate protein, a process that is repeated, resulting in polyubiquitin chain formation on the protein substrate. Polyubiquitin chains are subsequently recognized by the 26S proteasome, resulting in cleavage of the protein substrate into small peptides and the release of ubiquitin molecules. (B) Homologous polyubiquitin chains formed via linkages at lysine-48 of the presiding ubiquitin molecule result in a chain conformation that is recognized by the 26S proteasome. Conversely, polyubiquitin chains coupled via lysine-63 linkages yield chain conformations that are not recognized by the 26S proteasome; rather, these linkages alter the function of the protein substrate. Lys: Lysine; Ub: Ubiquitin.
Figure 2
Figure 2. Mechanisms of p53-mediated apoptosis
The transcription factor p53 regulates the induction of apoptosis by regulating BAX, PUMA and APAF-1 expression. The permeability of the mitochondria and subsequent release of cytochrome C is regulated by a balance between antiapoptotic (i.e., BCL-2) and proapoptotic (i.e., BAX) factors. The increase of the proapoptotic BAX and its effector molecule, PUMA, in response to p53, interacts with and overcomes the antiapoptotic BCL-2, resulting in the release of mitochondrial cytochrome C. Cytochrome C, together with ATP and APAF-1, acts to activate caspase 9 in the activation of apoptosis through the intrinsic pathway. APAF: Apoptotic protease-activating factor; BAX: BCL-2-associated X protein; BCL-2: B-cell lymphoma-2 protein; CHIP: Carboxyl terminus of Hsp70-interacting protein; MDM: Murine double minute; PUMA: p53-upregulated modulator of apoptosis.
Figure 3
Figure 3. Ubiquitin-proteasome system-mediated resulation of the nuclear factor-κB activation pathway
Activation of the multimeric IKK mediates the phosphorylation of IκB. The modified IκB is then recognized by the SCF-βTrCP E3 ubiquitin ligase and targeted for degradation via the ubiquitin-proteasome system, liberating the p50/p65 nuclear factor (NF)-κB dimer. This results in the exposure of a nuclear localization signal on p50/p65, previously obscured by IκB, promoting the nuclear translocation of p50/p65 and the subsequent activation of the NF-κB transcriptional program. Multiple pathways pertinent to cardiac hypertrophy and failure are activated by NF-κB-mediated transcription, such as cell adhesion, apoptosis, inflammation and immune-response signaling molecules. AGT: Angiotensinogen; CBF: Complement factor B; IAP: Inhibitor of apoptosis protein; ICAM: Intercellular adhesion molecule; IκB: Inhibitor of κB; IKK: IκB kinase complex; P: Phosphate; SAA: Serum amyloid A; SCF-βTrCP: Skip-Cullin-F box β-transducin repeat-containing protein; Ub: Ubiquitin; VCAM: Vascular cell adhesion molecule. Figure adapted from [65,66].
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