Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • MuRF and MuRF in http www

    2021-01-19

    MuRF1 and MuRF3 in cooperation with the E2 ubiquitin-conjugating enzymes UbcH5a, -b, and -c were found to mediate degradation of myosin heavy chain β/slow (MHC β/slow) and MHC IIa via UPS, both, in vitro and in vivo [60]. Mice lacking both MuRF1 and MuRF3 developed skeletal muscle myopathy and hypertrophic cardiomyopathy with sub-sarcolemmal MHC accumulation, myofibril fragmentation and diminished muscle performance, leading to myosin storage myopathy [60]. These findings identify MuRF1 and MuRF3 as key E3 ubiquitin ligases for UPS-dependent turnover of sarcomeric proteins and reveal a potential molecular basis for myosin storage myopathies. MuRF2 and MuRF3 are also known to have considerable functional overlap in binding to microtubules and in sarcomere formation in the process of 5-EdU of striated muscle cells [61]. Double knockout of MuRF1 and 3 in mice resulted in protein aggregate-associated myopathy in striated muscles [61]. Moreover, hearts from this mouse line displayed reduced systolic and diastolic function, increased expression of the MHC-β/slow, and calcium handling defects in the sarcomere. Interestingly, MuRF2 and MuRF3 reportedly protect heart against diabetic cardiomyopathy via non-proteasomal modification of peroxisome proliferator activating receptors (PPAR)-α/γ transcription factors, suggesting a pivotal role in metabolic pathways as well [62], [63]. 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 heart 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.