BRISC Deficiency Drives Heart Failure by Regulating β-Catenin K63 Ubiquitination.

BACKGROUND

Adverse cardiac remodeling and dysfunction are hallmarks of hypertensive heart failure, yet molecular mechanisms remain incompletely understood. K63-linked deubiquitination has emerged as a critical posttranslational regulatory process in cardiac remodeling. This study investigated the role of BRISC (BRCC3 [BRCA1/BRCA2-containing complex subunit 3] isopeptidase complex), a K63-specific deubiquitinase, in hypertensive cardiac remodeling.

METHODS

Expression of BRISC subunits was analyzed in hypertrophic human and murine hearts. Cardiac phenotypes were assessed in global and cardiomyocyte-specific Abro1 (Abraxas 2, BRISC complex subunit) knockout, cardiomyocyte-specific Abro1 overexpression, or Brcc3 knockout mice under baseline and Ang II (angiotensin II)-infused conditions. Ubiquitinome profiling, coimmunoprecipitation, immunoprecipitation-mass spectrometry, cleavage under targets and tagmentation analysis, ubiquitination site mutation, and rescue experiments were performed to identify BRISC substrates and mechanisms.

RESULTS

The BRISC scaffolding subunit ABRO1 was markedly downregulated in cardiomyocytes from hypertrophic hearts. Global or cardiomyocyte-specific Abro1 deletion led to spontaneous cardiac hypertrophy and contractile dysfunction, which were further aggravated by Ang II stimulation. Conversely, cardiomyocyte-specific Abro1 overexpression alleviated Ang II-induced cardiac remodeling and dysfunction. Knockout of Brcc3, the catalytic subunit of BRISC, phenocopied the cardiac abnormalities observed in Abro1-deficient mice. Mechanistically, ABRO1 directly interacted with β-catenin and cleaved K63-linked polyubiquitination chains at lysine 508, thereby restraining β-catenin nuclear accumulation and transcriptional activation. Pharmacological inhibition of β-catenin with ICG-001 (inhibitor of β-catenin/transcription factor mediated transcription) effectively rescued hypertensive cardiac remodeling and dysfunction caused by Abro1 deficiency.

CONCLUSIONS

BRISC acts as a critical K63-specific deubiquitinase that preserves cardiac homeostasis by restraining β-catenin overactivation. Targeting the BRISC-β-catenin axis may represent a novel therapeutic strategy for hypertensive heart failure.