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

Atrial fibrillation (AF) is a common arrhythmia associated with calcium (Ca2+) dysregulation. Ca2+/calmodulin-dependent protein kinase II-δ (CaMKII-δ) links Ca2+ 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 Ca2+ 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 Ca2+ 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.