• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • br TRIM TIF A RNF TRIM contains a RING


    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 K-115 kinase 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. We also found downregulation of TRIM32 in the hearts of dilated and hypertrophic cardiomyopathy patients in addition to TAC and phenylephrine treated mice [51]. TRIM32 and Dysbindin are known to interact in skeletal muscle, and we could confirm this interaction in cardiomyocytes as well. In cardiomyocytes, we found that by means of degradation, TRIM32 diminished the pro-hypertrophic effects of Dysbindin. Furthermore, we also found that TRIM32 protect apoptotic inducer p53 and degrades apoptotic inhibitor XIAP through upregulation of Caspase3 and Caspase7, thereby critically affecting cellular viability. Thus, we caution against putting TRIM32 forward as a therapeutic agent for cardiac hypertrophy, as this approach may have unwanted side effects due to increased apoptosis and reduced cell viability.
    TRIM72 (MG53) TRIM72, also known as Mitsugumin53 (MG53), possesses the most common structure of TRIM family members, with RING-Bbox1-Coiled coil-PRY/SPRY domains conservatively aligned from N-terminus to C-terminus. Mammalian Gene Collection (MGC) indicates two possible mammalian isoforms of TRIM72, one of which has been stated canonical and studied intensively in the context of preserving muscle integrity by sarcomere repair in skeletal and cardiac muscles [75]. MG53 is noted to play a central role in insulin resistance and thus metabolic disorders such as obesity and diabetes, with possible involvement in cardiovascular diseases like diabetic cardiomyopathy. MG53 has been reported to mediate degradation of both insulin receptor and insulin receptor substrate 1 (IRS1), causing dyslipidemia and hypertension besides metabolic disorders. In contrast, its ablation has been credited with preserving insulin receptor and IRS1. Thus, the mechanistic role of MG53 has been defined by investigating it as therapeutic agent for metabolic disorders and their cardiovascular complications [76]. In the heart, MG53 has been reported to be a vital player in both preconditioning and post-conditioning by activating PI3K-Akt-GSK3β and ERK1/2 cell survival signaling pathways in ischemia-reperfusion [77], [78]. For example, myocardial injury resulting from ischemia/reperfusion in the dysferlin murine KO model is strongly correlated with myocardial muscle impairment, resulting in a clinical trial in pediatric patients undergoing corrective heart surgery. Notably, human myocardium does not express MG53; suggesting rhMG53 might be an effective tool for muscular injuries in both skeletal and cardiac muscle repair [79]. Furthermore, MG53 (TRIM72) has been reported with dual roles, beneficial in phosphatidylserine-dependent prevention of skeletal muscle damage, protection of heart against ischemia-reperfusion injury, protection of other vital organs by membrane repair; while being maladaptive in the development of skeletal muscle insulin resistance, in the regulation of myogenesis [80]. This ‘Janus-faced’ nature of TRIM72 makes it a double-edged-sword for human diseases, taking in question its usage as a therapeutic agent.