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First published online 23 October 2008
doi: 10.1242/dev.022723

Development 135, 3881-3889 (2008)
Published by The Company of Biologists 2008
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Arginyltransferase regulates alpha cardiac actin function, myofibril formation and contractility during heart development

Reena Rai1, Catherine C. L. Wong2, Tao Xu2, N. Adrian Leu1, Dawei W. Dong3, Caiying Guo4, K. John McLaughlin1, John R. Yates, III2 and Anna Kashina1,5,*

1 Department of Animal Biology and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 The Scripps Research Institute, La Jolla, CA 92037, USA.
3 Florida Atlantic University, Boca Raton, FL 33431, USA.
4 Janelia Farm, Ashburn, VA 20147, USA.
5 Mari-Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

* Author for correspondence (e-mail: akashina{at}vet.upenn.edu)

Accepted 6 October 2008

Post-translational arginylation mediated by arginyltransferase (Ate1) is essential for cardiovascular development and angiogenesis in mammals and directly affects myocardium structure in the developing heart. We recently showed that arginylation exerts a number of intracellular effects by modifying proteins involved in the functioning of the actin cytoskeleton and in cell motility. Here, we investigated the role of arginylation in the development and function of cardiac myocytes and their actin-containing structures during embryogenesis. Biochemical and mass spectrometry analyses showed that alpha cardiac actin undergoes arginylation at four sites during development. Ultrastructural analysis of the myofibrils in wild-type and Ate1 knockout mouse hearts showed that the absence of arginylation results in defects in myofibril structure that delay their development and affect the continuity of myofibrils throughout the heart, predicting defects in cardiac contractility. Comparison of cardiac myocytes derived from wild-type and Ate1 knockout mouse embryos revealed that the absence of arginylation results in abnormal beating patterns. Our results demonstrate cell-autonomous cardiac myocyte defects in arginylation knockout mice that lead to severe congenital abnormalities similar to those observed in human disease, and outline a new function of arginylation in the regulation of the actin cytoskeleton in cardiac myocytes.

Key words: Protein arginylation, Heart development, Actin, Post-translational modifications, Myofibrils, Cardiac muscle


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