Junctophilin-2 prevents MURF1-mediated junctin ubiquitination and proteasome-dependent degradation to promote cardiomyocyte survival 4606

Description Junctophilin-2 (JP2) is required for the development, maturation and integrity of t-tubule system and Ca2+ regulation in cardiomyocytes. This study investigated if and how JP2 maintained junctin to prevent cardiomyocyte death under stress. Cardiomyocytes were exposed to different stress. Adenoviral vectors were used to manipulate expression of JP2 and junctin. Transverse aortic constriction (TAC)-induced heart failure models were created. Myocardial function was assessed by echocardiography. Stress decreased JP2 expression and concomitantly reduced junctin protein expression in cardiomyocytes. JP2 over-expression preserved junctin protein levels and attenuated cytosolic Ca2+ and apoptosis under stress. Notably, junctin over-expression prevented cardiomyocyte death under stress, whereas knockdown of junctin offset the protective effects conferred by JP2 over-expression. Mechanistically, JP2 blocked MURF1-junctin interaction, thereby preventing junctin ubiquitination and subsequent proteasome-dependent degradation. Mass spectrometry analysis identified multiple ubiquitination sites on junctin protein and the non-ubiquitinated junctin mutant was resistant to degradation. In TAC-induced heart failure model, transgenic over-expression of JP2 prevented junctin-MURF1 interaction and junctin ubiquitination and increased junctin protein levels. In summary, this study uncovers an unrecognized role of JP2 in preventing junctin ubiquitination and degradation and protecting cardiomyocytes Funding Sources This study was supported by the Heart & Stroke Foundation of Canada (G-17-0018361 to T.P.), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-04768 to T.P.), the Doctoral Innovation Projects of Jiangsu Province (Grant no. KYCX17_1816 to X.J.), the National Heart, Lung, and Blood Institute (R01 HL130346, HL157781, HL157741 L.S.S.). Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)