Citation:
Circ Res. 2010 Mar 19;106(5):880-90. Epub 2010 Jan 21
Abstract:
Rationale The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electrical coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy. Objective Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown. Methods Using a bioinformatic screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched ZO-associated protein). Results Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and ZO-1. In a yeast-two hybrid screen for additional binding partners of Myozap we identified myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity. Myozap, in turn, strongly activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a Rho-dependent fashion. Finally, in vivo knockdown of the Myozap orthologue in zebrafish led to severe contractile dysfunction and cardiomyopathy. Conclusions Taken together, these findings reveal Myozap as a previously unrecognized component of a Rho-dependent signaling pathway that links the intercalated disc to cardiac gene regulation. Moreover, its subcellular localization and the observation of a severe cardiac phenotype in zebrafish, implicate Myozap in the pathogenesis of cardiomyopathy.
Organism or Cell Type:
zebrafish
Delivery Method:
Microinjection