Abstract 18472: SUMO2 is a Novel Regulator of Calcineurin/NFAT Signaling and Cardiomyocyte Hypertrophy

Background: The calcineurin (Cn)/NFAT axis is a pivotal pathway in cardiomyocyte signaling in general and in the pathogenesis of cardiac hypertrophy and remodeling in particular. Methods & Results: The objective of this study was to systematically identify yet unknown modulators of the Cn/NFAT pathway. We thus screened a human cardiac cDNA-library (10 7 primary clones) using an NFAT-dependent luciferase (luc) reporter assay in C2C12 cells. Through several rounds of confirmation we identified SUMO2 as a novel strong activator of Cn/NFAT signaling. Moreover, we found SUMO2 to be a direct interaction partner of a nuclear calcineurin A pool. Further experiments in C2C12 cells indicated that SUMO2 mediates NFAT activation through Cn as shown by exaggerated NFAT activation even in the presence of constitutively active CnA (NFAT-luc: ΔCnA; 3.85-fold, p 1000 cells; all p Finally we studied the effect of a sumoylation-deficient mutant of SUMO2 (SUMO2ΔGG). Surprisingly, induction of Cn/NFAT and NRVCM hypertrophy was comparable to sumoylation-competent SUMO2 (ΔCnA+SUMO2ΔGG: 1.7-fold NFAT-luc, p Conclusions: In conclusion, we identified SUMO2 as a novel positive regulator of Cn/NFAT signaling and cardiomyocyte hypertrophy. Interestingly, these effects are independent of sumoylation, but rather mediated by retaining/tethering activated CnA in the nucleus.