Cardiomyocyte-Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination.

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Pathological cardiac hypertrophy is a major cause of heart failure.
• The precise molecular mechanisms driving cardiac hypertrophy are not fully understood.
• Deubiquitinating enzymes (DUBs) play critical roles in cellular processes, but their involvement in cardiac hypertrophy requires further investigation.

Purpose of the Study:

• To investigate the role and mechanism of the DUB ubiquitin-specific protease 20 (USP20) in cardiac hypertrophy.
• To identify USP20 substrates and downstream targets in cardiomyocytes.
• To explore the therapeutic potential of the USP20 pathway in mitigating cardiac hypertrophy.

Main Methods:

• Transcriptomic profiling of hypertrophic hearts to identify altered DUB expression.
• Co-immunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify USP20 substrates.
• Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing to identify STAT3 downstream targets.
• In vivo models of cardiac hypertrophy (Angiotensin II and TAC) and pharmacological inhibition (Stattic).

Main Results:

• USP20 expression is significantly downregulated in hypertrophic hearts and predominantly found in cardiomyocytes.
• USP20 deficiency exacerbates cardiac hypertrophy, while USP20 overexpression alleviates it.
• USP20 deubiquitinates STAT3, reducing its phosphorylation and nuclear translocation, thereby inhibiting STAT3's transcriptional activity at the CARM1 promoter.
• This leads to upregulated CARM1 expression and mitigated hypertrophy, with STAT3 confirmed as a key mediator.

Conclusions:

• A novel USP20/STAT3/CARM1 signaling axis in cardiomyocytes is identified.
• USP20 plays a protective role against cardiac hypertrophy by modulating STAT3 activity.
• Targeting the USP20/STAT3/CARM1 pathway holds therapeutic potential for treating cardiac hypertrophy and heart failure.