Characterization of arginylation branch of N-end rule pathway in G-protein-mediated proliferation and signaling of cardiomyocytes

Min Jae Lee, Dong Eun Kim, Adriana Zakrzewska, Young Dong Yoo, Su Hyeon Kim, Sung Tae Kim, Jai Wha Seo, Young Sook Lee, Gerald W. Dorn, Uh Taek Oh, Bo Yeon Kim, Yong Tae Kwon

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The N-end rule pathway is a proteolytic system in which destabilizing N-terminal amino acids of short lived proteins are recognized by recognition components (N-recognins) as an essential element of degrons, called N-degrons. In eukaryotes, the major way to generate N-degrons is through arginylation by ATE1 arginyl-tRNA-protein transferases, which transfer Arg from aminoacyl-tRNA to N-terminal Asp and Glu (and Cys as well in mammals). We have shown previously that ATE1-deficient mice die during embryogenesis with defects in cardiac and vascular development. Here, we characterized the arginylation-dependent N-end rule pathway in cardiomyocytes. Our results suggest that the cardiac and vascular defects in ATE1-deficient embryos are independent from each other and cell-autonomous. ATE1-deficient myocardium and cardiomyocytes therein, but not non-cardiomyocytes, showed reduced DNA synthesis and mitotic activity ~24 h before the onset of cardiac and vascular defects at embryonic day 12.5 associated with the impairment in the phospholipase C/PKC-MEK1-ERK axis of Gαq-mediated cardiac signaling pathways. Cardiac overexpression of Gαq rescued ATE1-deficient embryos from thin myocardium and ventricular septal defect but not from vascular defects, genetically dissecting vascular defects from cardiac defects. The misregulation in cardiovascular signaling can be attributed in part to the failure in hypoxia-sensitive degradation of RGS4, a GTPase-activating protein for Gαq. This study is the first to characterize the N-end rule pathway in cardiomyocytes and reveals the role of its arginylation branch in Gαq-mediated signaling of cardiomyocytes in part through N-degron-based, oxygen- sensitive proteolysis of G-protein regulators.

Original languageEnglish
Pages (from-to)24043-24052
Number of pages10
JournalJournal of Biological Chemistry
Issue number28
StatePublished - Jul 6 2012


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