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  • acetylcholine inhibitor MuRF interacts with four and a

    2019-09-07

    MuRF3 interacts with four-and-a-half LIM domain (FHL2) and γ-filamin leading to their degradation via UPS [64]. Conversely, abnormal aggregation of these proteins was observed in mice lacking MuRF3. Moreover, MuRF3-/- mice were found more prone to cardiac rupture after acute myocardial infarction (AMI) [64]. Recently, a clinical study aimed to find cardiac specific circulating E3 ubiquitin ligases that may aid in early prognosis of AMI identified increased blood plasma levels of MuRF1, MuRF3, and three other non-TRIM E3 ligases (Rnf207, Fbxo32 and Kbtbd10) in rats and AMI patients [65]. Interestingly, an unbiased metabolomics analysis revealed overlapping substrate specificities for all three MuRFs, where authors detected similarly altered metabolome for MuRF1-/-, MuRF2-/- and MuRF3-/- mouse hearts [66]. These findings suggest that via regulating metabolic pathways in the intact heart, MuRFs have pronounced protective effects on cardiac metabolism during disease states.
    TRIM8 (RNF27) TRIM8, also known as Ring finger 27, characteristically contains both B-boxes while lacks any C-terminal domain (Fig. 3). Recently, Chen et al., (2017) have found upregulation of TRIM8 in human dilated cardiomyopathy patients and hypertrophied mice [67]. TRIM8-deficient mice ameliorated pressure-overload effects after TAC preventing acetylcholine inhibitor failure. On the other hand, its cardiac specific overexpression exaggerated pressure overload hypertrophy after TAC leading to heart failure. Similarly, angiotensin-II mediated pro-hypertrophic effects were also exacerbated in vitro by TRIM8 overexpression. Mechanistically, pro-hypertrophic effects of TRIM8 were found to be mediated via poly-ubiquitination of TAK1 which further activates p38 and JNK1/2 hypertrophic signaling cascades. Prior to its cardiac role, TRIM8 has been intensively characterized in cancer associated studies [68], [69].
    TRIM21 Along with conserved RBCC frame at N-terminal, TRIM21 (Ro52) possesses PRY/SPRY domains at C-terminal (Fig. 3), which are necessary for its cytoplasmic localization and interaction with IRF3 [47]. It is a principle target for chronic autoimmune disorders like Sjögren\'s syndrome and systemic lupus erythematosus [70]. Recently, it has also been implicated in cardiac redox homeostasis by non-proteasomal ubiquitination, thus abrogating oligomerization of p62 [71]. TRIM21-deficient mice are protected from oxidative damage caused by pressure overload heart injury due to pronounced accumulation of p62, increased antioxidant response, and reduced ROS release.
    TRIM24 (TIF1A, RNF82) TRIM24 contains a RING-both B-boxes-coiled coil conserved structure at the N-terminus with bromo and PHD domains prior to C-terminal end (Fig. 3). This transcriptional intermediary factor is well studied in the context of transcriptional activation of nuclear receptor via activation function 2 (AF2), owing to its nuclear presence and thus capability to indulge with histones. We recently discovered that TRIM24 is consistently upregulated in the hearts of human patients suffering from hypertrophic and dilated cardiomyopathies [51]. We additionally identified TRIM24 as a bona fide cardiac binding partner of a pro-hypertrophic protein Dysbindin [51], [72]. Functionally, we found that binding of Dysbindin to TRIM24 protects it from proteasomal degradation due to TRIM32. This in turn adds to the Dysbindin-mediated activation of RhoA-SRF signaling and cardiomyocyte hypertrophy [51].
    TRIM32 TRIM32 harbors RING-B-box-coiled coil tripartite motif at its N-terminus whit six C-terminal NHL repeats (Fig. 3). Its genetic mutations have been linked with muscular dystrophies like Limb girdle muscular dystrophy, Bardet-Biedl syndrome, sarcotubular myopathy, and dystrophic myopathy [73]. TRIM32 has recently been shown to play a protective role in aortic banding mediated pathological hypertrophy by blocking AKT-mediated signaling to prevent heart failure [74]. Using a gain of function approach Chen et al. demonstrated attenuation of excessive hypertrophy and altered cellular architecture of heart in mice overexpressing TRIM32, prompting them to suggest it as a novel therapeutic target in cardiac hypertrophy and heart failure.