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1.
Cells ; 9(11)2020 10 31.
Article in English | MEDLINE | ID: mdl-33142804

ABSTRACT

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5-7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin's role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.


Subject(s)
Cardiomegaly/genetics , Cardiomegaly/metabolism , Dysbindin/genetics , Dysbindin/metabolism , Muscle Proteins/metabolism , Myocytes, Cardiac/metabolism , Animals , Cytosol/metabolism , Gene Expression Regulation , Hypertrophy/physiopathology , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Organelle Biogenesis , Protein Binding , Schizophrenia/genetics , Schizophrenia/metabolism , Serum Response Factor/metabolism , Signal Transduction , Vesicular Transport Proteins/metabolism , rhoA GTP-Binding Protein/metabolism
2.
Commun Biol ; 3(1): 562, 2020 10 09.
Article in English | MEDLINE | ID: mdl-33037313

ABSTRACT

Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.


Subject(s)
Cardiomegaly/metabolism , Myocarditis/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Calcineurin/metabolism , Cardiomegaly/enzymology , Cardiomegaly/prevention & control , Humans , Immunoprecipitation , Mice , Microscopy, Fluorescence , Myocarditis/enzymology , Myocarditis/prevention & control , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/metabolism , RAW 264.7 Cells , Rats , Rats, Wistar , STAT1 Transcription Factor/metabolism , Signal Transduction , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation , Ubiquitin-Protein Ligases/physiology
3.
J Biol Chem ; 292(24): 10180-10196, 2017 06 16.
Article in English | MEDLINE | ID: mdl-28465353

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.


Subject(s)
Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Hypertrophic/metabolism , Carrier Proteins/metabolism , Dystrophin-Associated Proteins/metabolism , Myocytes, Cardiac/metabolism , Serum Response Factor/metabolism , Transcription Factors/metabolism , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Animals, Newborn , Apoptosis , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Hypertrophic/pathology , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/genetics , Cells, Cultured , Dysbindin , Dystrophin-Associated Proteins/chemistry , Dystrophin-Associated Proteins/genetics , HEK293 Cells , Humans , Myocytes, Cardiac/cytology , 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 , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Tripartite Motif Proteins/antagonists & inhibitors , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics
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