Abstract P2020: Binding Of Filamin C With Actin Is Essential For Cardiac Development And Function

Abstract

Filamin C (FLNC), a filamin family member predominantly expressed in striated muscles, is crucial for bridging the extracellular matrix and the cytoskeleton in cardiomyocytes (CMs), and the maintenance of heart integrity and function. FLNC consists of an N-terminal actin-binding domain (ABD) and 24 immunoglobulin (Ig)-like repeat domains at C-terminus. Many pathogenic mutations on N-terminal ABD have been found in patients with cardiomyopathies. However, little is known about how the actin-binding activity intrinsically contributes to the function of FLNC in mammalian hearts. Using structure-based design, we mutated two key actin binding residues F93 and L98 into Ala and Glu respectively in FLNC ABD (F93A/L98E) and show that the mutations completely disrupted the FLNC-actin interaction. We then generated a knock-in mouse model, demonstrating that loss of FLNC-actin interaction in embryonic CMs led to embryonic lethality and cardiac developmental defects displayed by ventricular rupture and reduced CM proliferation. Moreover, disruption of FLNC-actin interaction in adult CMs resulted in severe DCM phenotypes and reduced survival rate, accompanied with aberrant levels of key cytoskeleton components. These phenotypes resemble those of FLNC knockout mouse models, demonstrating a vital role of the FLNC-actin binding in the function of CMs. Our results also provide a foundation for understanding the mutation-induced cardiomyopathies associated with dysregulation of FLNC ABD-actin interaction.