Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo

Thalia S. Seeger, Derk Frank, Claudia Rohr, Rainer Will, Steffen Just, Christine Grund, Robert Lyon, Mark Luedde, Manfred Koegl, Farah Sheikh, Wolfgang Rottbauer, Werner W. Franke, Hugo A. Katus, Eric N. Olson, Norbert Frey

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Rationale: The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric 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 and Results: Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens-1. In a yeast 2-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 ortholog 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.

Original languageEnglish (US)
Pages (from-to)880-890
Number of pages11
JournalCirculation research
Volume106
Issue number5
DOIs
StatePublished - Mar 19 2010

Keywords

  • Cardiac
  • Cardiomyopathies
  • Myocytes
  • Serum response factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Seeger, T. S., Frank, D., Rohr, C., Will, R., Just, S., Grund, C., Lyon, R., Luedde, M., Koegl, M., Sheikh, F., Rottbauer, W., Franke, W. W., Katus, H. A., Olson, E. N., & Frey, N. (2010). Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo. Circulation research, 106(5), 880-890. https://doi.org/10.1161/CIRCRESAHA.109.213256