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.