BRISC-Mediated PPM1B-K63 Deubiquitination and Subsequent TGF-β Pathway Activation Promote High-Fat/High-Sucrose Diet-Induced Arterial Stiffness.

Summary

The study identifies ABRO1 within the BRISC complex as a YAP-dependent partner that undergoes liquid–liquid phase separation with YAP and PPM1B to promote PPM1B K63 deubiquitination, activating TGF-β signaling and arterial stiffness under HFHSD. Smooth muscle-specific PPM1B overexpression attenuated stiffness in a K326/K63-ubiquitination–dependent manner, highlighting a druggable pathway.

Key Findings

• Smooth muscle cell-specific PPM1B overexpression attenuated HFHSD-induced arterial stiffness in a PPM1B K326/K63 polyubiquitination-dependent manner.
• ABRO1 directly bound YAP and underwent liquid–liquid phase separation with YAP and PPM1B to promote PPM1B K63 deubiquitination.
• PPM1B deubiquitination mechanisms were elucidated, implicating TGF-β pathway activation in HFHSD-induced arterial stiffness and nominating a therapeutic target.

Clinical Implications

Targeting the ABRO1–YAP–PPM1B–BRISC axis or modulating PPM1B K63-linked ubiquitination may reduce arterial stiffness in metabolic syndrome, suggesting strategies beyond blood pressure control.

Limitations

• Incomplete mechanistic details in abstract and reliance on preclinical models; human validation remains to be shown.
• The specific downstream causal chain from PPM1B deubiquitination to TGF-β activation and stiffness in humans needs clinical correlation.

Future Directions

Translate findings to human tissue/biomarkers; test pharmacologic modulators of BRISC/ABRO1–YAP–PPM1B; and evaluate effects on arterial stiffness endpoints clinically.