Microtubules Sequester Acetylated YAP in the Cytoplasm and Inhibit Heart Regeneration

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Epigenetics and Post-Translational Modifications

Background:

• Yes-associated protein (YAP) is crucial for cardiomyocyte proliferation and heart regeneration.
• YAP's nuclear-cytoplasmic shuttling is vital for its function, but mechanisms after myocardial infarction are unclear.

Purpose of the Study:

• To elucidate the role of YAP acetylation in regulating its subcellular localization post-myocardial infarction.
• To investigate the impact of YAP acetylation on cardiac regeneration.

Main Methods:

• Identified YAP acetylation at K265 using mass spectrometry.
• Utilized adeno-associated virus to express YAP mutants (K265R, K265Q) in mouse hearts.
• Generated YAP-K265R mutant cell lines and mice for functional studies.
• Investigated YAP-TUBA4A interactions and microtubule network dynamics.

Main Results:

• YAP is acetylated by CBP/P300 and deacetylated by the NAMPT/NAD+/SIRTuins axis in cardiomyocytes.
• Myocardial infarction increases YAP acetylation, promoting its cytoplasmic localization.
• YAP K265R mutation enhances cardiac regeneration and YAP nuclear localization.
• Acetylated YAP interacts with TUBA4A, leading to cytoplasmic sequestration.

Conclusions:

• Decreased sirtuin activity post-myocardial infarction enhances YAP acetylation at K265.
• Increased TUBA4A network sequesters acetylated YAP in the cytoplasm, impairing cardiac regeneration.