br Expression data suggest involvement of additional TRIMs
Expression data suggest involvement of additional TRIMs in heart function Given the complexity of the cardiac function, involved molecular pathways and processes, and the fact that only a few of the TRIMs have thus far been shown to have a cardiac role, we hypothesized that there would be more TRIMs mediating important functions in the heart. Along these lines, we checked the Malotilate of all known human TRIMs in various heart regions using human affymetrix data publicly available with Genevestigator (https://genevestigator.com/gv/). Several of the yet uncharacterized TRIMs were found to be significantly expressed in the heart, such as TRIM18, TRIM22, TRIM42, TRIM49, TRIM67, TRIM69, and TRIM73 (Fig. 5A). We additionally determined the expression of all TRIMs present in myocardium under cardiac disease settings like heart failure, cardiomyopathies, myocardial infarction, and atrial fibrillation. Interestingly, in addition to known cardiac TRIMs, several other TRIMs were found to be differentially regulated in these disease conditions (Fig. 5B). Moreover, majority of the TRIMs which were found significantly expressed in the heart e.g. TRIM17, TRIM18, TRIM22, TRIM42, TRIM48, TRIM49, TRIM67, TRIM69, and TRIM73, were also part of the dysregulated TRIMs in cardiac disease conditions. Although these bioinformatics findings need experimental validations, overall, these data suggests the potential of more cardiac specific research for TRIMs in disease context (Fig. 5B).
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 aggregates . 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).