Cereblon contributes to cardiac dysfunction by degrading Ca(v)1.2 alpha

Aims Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Ca(v)1.2 alpha during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Ca(v)1.2 alpha activity and examining how it can serve as a target to address myocardial dysfunction. Methods and results Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbn(fl/fl)/Myh6(Cre+)) exhibited enhanced cardiac contractility with increased LTCC current (I-CaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Ca(v)1.2 alpha. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Ca(v)1.2 alpha. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Ca(v)1.2 alpha and decreased I-CaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Ca(v)1.2 alpha and enhanced I-CaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Conclusion Cereblon selectively degrades Ca(v)1.2 alpha, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics. Key question What is the substrate-binding partner of cereblon (CRBN) in the heart? What is the role of CRBN in the heart? What is the link between CRBN and heart failure with reduced ejection fraction (HFrEF)? Key finding Cereblon directly binds and degrades Ca(v)1.2 alpha through ubiquitination. Cereblon regulates cardiac contractility and Ca(v)1.2 alpha current density by selectively degrading Ca(v)1.2 alpha. Cereblon is highly expressed in human HFrEF patients, and CRBN knockout enhanced cardiac contractility to confer cardioprotection in HFrEF. Take-home message Cereblon modulates cardiac function by altering Ca(v)1.2 alpha current density and CRBN-targeting therapy could serve as a novel strategy for future HFrEF therapeutics. [GRAPHICS] .