TRIM24 protein promotes and TRIM32 protein inhibits cardiomyocyte hypertrophy via regulation of dysbindin protein levels

J Biol Chem. 2017 Jun 16;292(24):10180-10196. doi: 10.1074/jbc.M116.752543. Epub 2017 May 2.

Abstract

We have previously shown that dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling. We have now performed a yeast two-hybrid screen using dysbindin as bait against a cardiac cDNA library to identify the cardiac dysbindin interactome. Among several putative binding proteins, we identified tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another tripartite motif (TRIM) family protein, TRIM32, has been reported earlier as an E3 ubiquitin ligase for dysbindin in skeletal muscle. Consistently, we found that TRIM32 also degraded dysbindin in neonatal rat ventricular cardiomyocytes as well. Surprisingly, however, TRIM24 did not promote dysbindin decay but rather protected dysbindin against degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF signaling and hypertrophy due to dysbindin, whereas TRIM24 promoted these effects in neonatal rat ventricular cardiomyocytes. This study also implies that TRIM32 is a key regulator of cell viability and apoptosis in cardiomyocytes via simultaneous activation of p53 and caspase-3/-7 and inhibition of X-linked inhibitor of apoptosis. In conclusion, we provide here a novel mechanism of post-translational regulation of dysbindin and hypertrophy via TRIM24 and TRIM32 and show the importance of TRIM32 in cardiomyocyte apoptosis in vitro.

Keywords: SRF-signaling; TRIM24; TRIM32; X-linked inhibitor of apoptosis protein (XIAP); apoptosis; cardiac hypertrophy; cardiac signaling; cardiomyocyte; cardiomyopathy; dysbindin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Hypertrophic / metabolism*
  • Cardiomyopathy, Hypertrophic / pathology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Dysbindin
  • Dystrophin-Associated Proteins / chemistry
  • Dystrophin-Associated Proteins / genetics
  • Dystrophin-Associated Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Stability
  • Proteolysis
  • RNA Interference
  • Rats
  • Rats, Wistar
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Serum Response Factor / agonists
  • Serum Response Factor / antagonists & inhibitors
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism*
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins / antagonists & inhibitors
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Carrier Proteins
  • DTNBP1 protein, human
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • SRF protein, human
  • Serum Response Factor
  • TRIM24 protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM32 protein, human
  • Ubiquitin-Protein Ligases