Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling.

Summary

CRYAB Ser59 phosphorylation drives phase-separated condensates toward pathological aggregates, causing desmin mislocalization and promoting cell death and adverse LV remodeling after MI. A phosphorylation-deficient S59A knock-in rescued post-MI function, and 25-hydroxycholesterol attenuated Ser59 phosphorylation and adverse remodeling, nominating a druggable pathway.

Key Findings

• Desmin and sarcomeric proteins mislocalized into aggregates in human ischemic cardiomyopathy and post-MI mouse hearts.
• CRYAB Ser59 phosphomimetic (S59D) reduced condensate fluidity, increased aggregates and cell death; S59A restored fluidity and reduced aggregates.
• S59A knock-in mice were protected from post-MI LV dysfunction; 25-hydroxycholesterol reduced Ser59 phosphorylation and adverse remodeling.

Clinical Implications

Targeting CRYAB Ser59 phosphorylation and condensate fluidity (e.g., via 25-hydroxycholesterol or kinase modulation) could mitigate adverse remodeling after MI, complementing current neurohormonal and device therapies.

Limitations

• Preclinical models; clinical efficacy and safety of targeting CRYAB phosphorylation remain untested.
• Kinases/phosphatases governing Ser59 in human myocardium need mapping for translational targeting.

Future Directions

Identify upstream modifiers of CRYAB Ser59, test small molecules that restore condensate fluidity, and evaluate biomarker signatures of condensatopathy in post-MI patients.