The Deubiquitinase UCHL1 Drives Susceptibility to Atrial Fibrillation by Stabilizing CaMKII‐δ

ABSTRACT Atrial fibrillation (AF) is a common arrhythmia associated with calcium (Ca 2+ ) dysregulation. Ca 2+ /calmodulin‐dependent protein kinase II‐δ (CaMKII‐δ) links Ca 2+ handling to arrhythmogenesis, but whether deubiquitination regulates its stability in AF remains unclear. We established an AF model by infusing angiotensin II (Ang II) for 3 weeks in atrial cardiomyocyte‐specific ubiquitin C‐terminal hydrolase L1 (UCHL1)‐knockout (CKO) and recombinant adeno‐associated virus serotype 9 (rAAV9)‐UCHL1‐overexpressing mice. UCHL1 was markedly upregulated in atria from Ang II‐infused mice and patients with AF. UCHL1‐CKO attenuated Ang II‐induced atrial remodeling and AF susceptibility, reduced CaMKII‐δ stability, and improved Ca 2+ handling, whereas UCHL1 overexpression produced the opposite effects. Mechanistically, UCHL1 bound to and deubiquitinated CaMKII‐δ at K251, preventing proteasomal degradation and thereby enhancing ryanodine receptor type 2 (RyR2) phosphorylation and Ca 2+ mishandling. The ubiquitination‐deficient CaMKII‐δ‐K251R mutant aggravated AF, whereas CaMKII‐δ knockdown or inhibition reduced the proarrhythmic effects of UCHL1 overexpression. Furthermore, the UCHL1 inhibitor 6RK73 reduced AF inducibility in mice. These findings identify UCHL1‐mediated stabilization of the CaMKII‐δ–RyR2 axis as a mechanism of AF and support UCHL1 as a potential therapeutic target.