Abstract 118: PP2A/HSP70 Dynamically Regulates HDAC2 Phosphorylation and its Activity in Cardiac Hypertrophy
Rationale: Cardiac hypertrophy is an adaptation for increased hemodynamic demands by underlying diseases and histone deacetylase (HDAC) 2 phosphorylation and following its activation are closely associated with those of process. Recently, we have demonstrated that the acetylation of HDAC2 K75 could induce S394 phosphorylation; however, specific mechanism for inter-modifications regulation in the single protein largely remains unclear.
Objective: We aimed to delineate the regulation mechanism how K75 acetylation modulates S394 phosphorylation and which phosphatase regulates HDAC2 phosphorylation in the cardiac hypertrophy.
Methods and Results: We found that the catalytic subunit of protein phosphatase (PP) 2A bound to HDAC2 in the H9c2 cell. PP2A kept HDAC2 unphosphorylated in the absence of hypertrophic stresses. Hypertrophic stresses-induced activation of pCAF, however, induced HDAC2 K75 acetylation, which then allowed PP2A to dissociate from HDAC2. This dissociation leads CK2α1 to bind to and phosphorylate HDAC2. Hypertrophic stresses induced HSP70 which then preferentially bound to phosphorylated HDAC2 rather than to unphosphorylated one. Forced expression of PP2CA not only reduced enzyme activity of HDAC2 but inhibited hypertrophic response in the cardiomyocytes. On the other hand, HSP70 bound to phosphorylated HDAC2 in order to mask the phosphor-HDAC2 from PP2CA. HDAC2 phosphorylation and following activation of intrinsic activity were regulated by binding of PP2CA to HDAC2. PP2A functioned as a negative regulator for cardiac hypertrophy by targeting of HDAC2 S394 phosphorylation.
Conclusion: Taken together, HDAC2 forms a complex with PP2A in the absence of hypertrophic stresses and remains inactivated. HDAC2 acetylation results in both detachment of PP2A and binding of CK2α1 for phosphorylation, which is maintained by the association with HSP70 during development of cardiac hypertrophy.
Author Disclosures: G. Eom: None. S. Yoon: None. H. Min: None. Y. Nam: None. D. Kwon: None. H. Kook: None.
- © 2015 by American Heart Association, Inc.