RING Finger Protein RNF207: A Novel Regulator of Cardiac Excitation [Protein Synthesis and Degradation]

October 3rd, 2014 by Roder, K., Werdich, A. A., Li, W., Liu, M., Kim, T. Y., Organ-Darling, L. E., Moshal, K. S., Hwang, J. M., Lu, Y., Choi, B.-R., MacRae, C. A., Koren, G.

Two recent studies [Newton-Cheh et al., Nature Genetics 41, 399-406 (2009); Pfeufer et al., Nature Genetics 41, 407-414 (2009)] identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in APD prolongation, occasionally a 2:1 atrioventricular block and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened APD. Using transfections of U-2 OS and HEK293 cells, western blot and immunocytochemistry data demonstrate that RNF207 and the HERG (human ether-a-go-go-related gene) potassium channel interact and co-localize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by approximately 30-50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, co-expression of RNF207 and HSP70 increased HERG expression as compared to HSP70 alone. This effect was dependent on the C-terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner.