BRISC Deficiency Drives Heart Failure by Regulating β-Catenin K63 Ubiquitination
Lu Liu1, Guang-Ming Ren2, Chen Chen2
1Department of Nutrition and Food Hygiene, Beijing Key Laboratory of Environment and Aging, School of Public Health (L.L., W.-H.N., L.W.).
Insights
The BRISC complex, a K63-specific deubiquitinase, prevents hypertensive heart failure by regulating beta-catenin. Targeting this BRISC-beta-catenin pathway offers a new therapeutic strategy for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biochemistry
Background:
- Hypertensive heart failure is characterized by adverse cardiac remodeling and dysfunction, with underlying molecular mechanisms not fully elucidated.
- K63-linked deubiquitination is recognized as a key posttranslational regulatory mechanism influencing cardiac remodeling.
- The BRISC (BRCC3 isopeptidase complex), a deubiquitinase specific for K63-linked ubiquitin chains, was investigated for its role in hypertensive cardiac remodeling.
Purpose of the Study:
- To investigate the role of the BRISC complex, specifically its scaffolding subunit ABRO1 and catalytic subunit BRCC3, in the context of hypertensive cardiac remodeling.
- To elucidate the molecular mechanisms by which BRISC influences cardiac function and structure under hypertensive conditions.
- To identify potential therapeutic targets within the BRISC-mediated regulatory pathway for hypertensive heart failure.
Main Methods:
- Analysis of BRISC subunit expression in human and murine hypertrophic hearts.
- Assessment of cardiac phenotypes in genetically modified mice (global/cardiomyocyte-specific Abro1 knockout/overexpression, Brcc3 knockout) under baseline and angiotensin II-infused conditions.
- Utilized ubiquitinome profiling, coimmunoprecipitation, immunoprecipitation-mass spectrometry, CUT&Tag, ubiquitination site mutation, and rescue experiments to identify BRISC substrates and mechanisms.
Main Results:
- Downregulation of the BRISC scaffolding subunit ABRO1 was observed in cardiomyocytes of hypertrophic hearts.
- Abro1 deficiency in mice led to spontaneous cardiac hypertrophy and contractile dysfunction, exacerbated by angiotensin II.
- Abro1 overexpression protected against angiotensin II-induced cardiac remodeling, while Brcc3 knockout mimicked Abro1 deficiency phenotypes, highlighting BRISC's critical role.
- ABRO1 was found to directly interact with β-catenin, cleaving K63-linked polyubiquitination at K508 to inhibit β-catenin nuclear accumulation and transcriptional activity.
- Pharmacological inhibition of β-catenin rescued cardiac dysfunction in Abro1-deficient mice.
Conclusions:
- The BRISC complex functions as a crucial K63-specific deubiquitinase that maintains cardiac homeostasis by suppressing β-catenin overactivation.
- The BRISC-β-catenin axis represents a promising novel therapeutic target for managing hypertensive heart failure.
- Understanding the deubiquitination activity of BRISC in cardiac remodeling provides insights into preventing and treating heart failure.
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.
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