br Concluding remarks and prospective Cardiac proteinopathy
Concluding remarks and prospective Cardiac proteinopathy, a more common disease condition and more frequent cause of cardiomyocyte decay than previously thought, is largely neglected and no effective therapy exists yet. Protein quality control and protein degradation via autophagy or the ubiquitination proteasome system are essential mechanisms in the maintenance of cellular homeostasis. Perturbations of these tightly regulated pathways are involved in several diseases, such as, Parkinson\'s and Alzheimer\'s disease, cancer, Crohn´s disease, skeletal myopathies, and heart diseases including cardiac hypertrophy and failure. Moreover, several inherited cardiomyopathies are associated with disruption of autophagy and/or pathological protein aggregation, such as mutations in the sarcomeric z-disc proteins BAG3 or desmin and its chaperone α-B-crystallin, leading to proteotoxicity and dilated cardiomyopathy in affected patients. Interestingly, several anti-cancer drugs such as tyrosine kinase inhibitors (e.g. imatinib), anthracyclines (e.g. doxorubicin) or proteasome inhibitors (e.g. bortezomib) impair the UPS or autophagy, thereby secondarily causing cardiomyopathy as a side effect. Thus, there is an urgent need to further investigate and develop innovative therapeutic approaches of cardiomyopathy and heart failure in the context of proteinopathies. Modulation of E3 ligases in the heart poses great potential as an alternative and specific therapeutic strategy. For example, an unbiased high-throughput screen by Robbins lab has recently identified several potential candidates including E3 ligases that accelerate or attenuate formation of cardiomyocyte protein carboxypeptidase . Similarly, downregulation of TRIM8 or TRIM21 is proven to be beneficial and suggested as potential therapeutic approaches for pathological hypertrophy and heart failure. Moreover, it is also important to understand that E3-ligases selectively ubiquitinates distinct target proteins because of the presence of distinct target binding domains. This very fact can be therapeutically exploited, (i) to activate or supplement an E3-ligase that can selectively degrade a misfolded or unfolded protein of interest to reduce or dissolve protein aggregates formed, and (ii) to activate or inhibit downstream signaling pathways or cellular processes, in order to improve cardiac function in heart disease conditions.
Acknowledgment This work is supported by the German Research Foundation (DFG) grant RA2717/2–1 (AYR and NF).
The ubiquitin proteasome system The ubiquitin proteasome system (UPS) plays a significant role in the regulation of cell growth and survival, in addition to maintaining cellular homeostasis. By means of the UPS, cells can precisely and temporally degrade approximately 80% of the entire proteome. However, failure to do so results in numerous diseases, including hematological malignancies and cancer , , . Protein ubiquitylation is catalyzed by a three-step enzymatic cascade in which the ubiquitin is first activated by an E1 enzyme (ubiquitin-activating enzyme) and subsequently transferred to an E2 enzyme (ubiquitin-conjugating enzyme). Finally, ubiquitin is attached to a specific substrate that is selected by an E3 ubiquitin ligase that governs substrate specificity. One of the principal outputs of protein ubiquitylation is degradation via the proteasome complex. The proteasome comprises of a regulatory 19S cap complex that unfolds the substrates in an ATP-dependent manner and a catalytic 20S core complex that has proteolytic activities . Proteins that are tagged by the ubiquitin chains are recognized, deubiquitylated, and unfolded by the 19S complex and subsequently fed through the inner channel of the 20S proteasome chamber, which cleaves proteins into peptides . Ubiquitin contains total of eight attachment sites (seven lysine residues and the amino N-terminus) for the formation of polymeric chains . Substrates can be modified at multiple lysine residues with a single ubiquitin molecule (multimono-ubiquitylation), or a single ubiquitin molecule can build a chain using ubiquitin as substrate . Moreover, ubiquitin chains can be homotypic conjugates where they are elongated through the same lysine as in Lys11-, Lys48-, Lys63-linked chains or methionine (M-linked) residue, as in linear chains . Lys-11-linked chains and Lys48-linked chains target proteins for proteosomal degradation , . On the other hand, Lys-63-linked chains regulate DNA repair, endocytic trafficking, NF-κB activation, and assembling a signaling complex for mRNA translation , , , . M-linked chains or linear ubiquitin chains play an important role in immune, inflammatory and NF-κB signaling , , . The significance and the roles of Lys6-, Lys27-, Lys29-, Lys33- linked chains are still poorly understood although, recently, they have been implicated in DNA repair, trans-Golgi trafficking, and mitochondria damage , .