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Related Experiment Video

Updated: Mar 7, 2026

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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.).

Hypertension (Dallas, Tex. : 1979)
|March 6, 2026
PubMed
Summary
This summary is machine-generated.

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.

Keywords:
angiotensin IIcardiomegalycateninsdeubiquitinating enzymesheart failure

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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.