Abstract
Abstract P1149: Junctophilin-2 Promotes Cardiomyocyte Survival By Blocking Murf1-mediated Junctin Ubiquitination And Proteasome-dependent Degradation
Circulation research, Vol.133(Suppl_1)
08/04/2023
DOI: 10.1161/res.133.suppl_1.P1149
Abstract
Abstract only Background: Junctophilin-2 is required for the development, maturation and integrity of the t-tubule system and the gating stability of RyR2 in cardiomyocytes. This study investigated whether and how junctophilin-2 maintained junctin, a scaffold protein stabilizing RyR2, to prevent cardiomyocyte death under stress. Methods: Cardiomyocytes were exposed to conditions of stress including palmitate, doxorubicin, or hypoxia/re-oxygenation. Adenoviral vectors were employed to manipulate expression of junctophilin-2 and junctin in cardiomyocytes. Molecular/cellular/biochemical analyses were conducted. Results: Different conditions of stress decreased junctophilin-2 expression through aberrant autophagy and concomitantly induced a reduction of junctin protein in cardiomyocytes. Over-expression of junctophilin-2 preserved the protein levels of junctin and attenuated cytosolic Ca 2+ and apoptosis in cardiomyocytes under stress. Knockdown of junctophilin-2 reproduced the detrimental phenotypes of stress in cardiomyocytes. Notably, over-expression of junctin prevented cardiomyocyte death under stress whereas knockdown of junctin offset the protective effects conferred by junctophilin-2 over-expression. Mechanistically, junctophilin-2 blocked MURF1-junctin interaction thereby preventing junctin ubiquitination and proteasome-dependent degradation. Mass spectrometry analysis identified multiple ubiquitination sites on the junctin protein and the non-ubiquitinated junctin mutant (K8R/K102R/K107R/K140R) was resistant to degradation. Conclusions: This study uncovers an unrecognized role of junctophilin-2 in preventing junctin ubiquitination and degradation in maintaining cytosolic Ca 2+ homeostasis. Junctophilin-2 and junctin represent two new survival factors of cardiomyocytes and thus, may be new therapeutic targets for cardiac protection.
Details
- Title: Subtitle
- Abstract P1149: Junctophilin-2 Promotes Cardiomyocyte Survival By Blocking Murf1-mediated Junctin Ubiquitination And Proteasome-dependent Degradation
- Creators
- Xiaoyun JiYifan HuangRui Ni - CanadaGuo-Chang Fan - University of CincinnatiDong Zheng - Soochow UniversityDouglas L Jones - Western UniversityLong-Sheng Song - University of IowaSubrata Chakrabarti - Western UniversityZhaoliang SuTianqing Peng - Western University
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.133(Suppl_1)
- DOI
- 10.1161/res.133.suppl_1.P1149
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/04/2023
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Cardiovascular Medicine; Internal Medicine; Biochemistry and Molecular Biology
- Record Identifier
- 9984480136802771
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