Functional characterization of TRIM24 and TRIM32 proteins in the heart through their interaction with Dysbindin

Ubiquitination is one of the important post-translational modifications and a vital cellular process involved in various tasks of targeted protein degradation via the Ubiquitin-Proteasome system (UPS), intracellular signaling, cell death, transcriptional control, etc. Importantly, it prevents the aggregation of non-functional, misfolded, and potentially harmful proteins to maintain protein homeostasis. Ubiquitination is accomplished by the concerted action of three enzymatic steps involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. Tripartite motif-containing (TRIM) proteins are one of the integral members of E3 ubiquitin ligases in metazoans, modulating essential cellular pathways. For long, MuRFs (Muscle ring finger proteins) were the most extensively studied TRIMs for their cardiac function. Recent advances in the field, however, have demonstrated broader and ever-increasing reports of various TRIM E3 ligases in the (patho-) physiology of the heart. A schizophrenia susceptibility protein, Dysbindin was reported by our group to also play a role in the heart and to be the robust inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling pathway. A Yeast two-hybrid screen was performed using Dysbindin as bait against a human cardiac cDNA library to identify the cardiac Dysbindin interactome. Among several putative binding proteins, TRIM24 was identified and confirmed to be interacting with Dysbindin by experimental methods of co-immunoprecipitation and co-immunostaining. Another TRIM family protein, TRIM32, has earlier been reported as an E3 ubiquitin ligase for Dysbindin in skeletal muscle. Consistently, TRIM32 degraded Dysbindin in neonatal rat ventricular cardiomyocytes (NRVCMs) as well. Surprisingly, however, TRIM24 did not promote Dysbindin decay but rather protected Dysbindin against possible degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF signaling and hypertrophy through Dysbindin decay, whereas TRIM24 promoted Dysbindin-induced hypertrophic effects in NRVCMs. Further experiments in this study also signify 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 here provide 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.


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