JP2 and JCN Crosstalk Abrogate MURF1-Mediated JCN Ubiquitination and Degradation in Cardiomyocytes
Junctophilin-2 (JP2) and junctin (JCN) are key proteins in maintaining calcium homeostasis in cardiomyocytes. Both are reduced in diseased hearts while overexpression of JP2 mitigates heart failure. This study demonstrates that JP2 and JCN are reduced in cardiomyocytes under stress, leading to intracellular calcium dysregulation and subsequent cell death. JP2 binds JCN, thereby blocking muscle ring finger protein-1 (MURF1)-JCN interaction and subsequently preventing MURF1-mediated JCN ubiquitination and degradation in cardiomyocytes. Thus, JP2 overexpression and MURF1 inhibition similarly preserve JCN protein and attenuate myocardial injury and remodeling, and improve myocardial function in preclinical animal models of lipid overload-induced cardiomyopathy and transverse aortic constriction-induced heart failure. Disruption of the JP2-JCN axis represents an important mechanism underlying heart disease and may serve as a potential therapeutic target for cardiac protection.
Authors
- Guo‐Chang Fan (ORCID: https://orcid.org/0000-0002-0439-8277)
- Zhaoliang Su (ORCID: https://orcid.org/0000-0002-5998-5575)
- Jinxi Wang (ORCID: https://orcid.org/0000-0002-0291-002X)
- Subrata Chakrabarti (ORCID: https://orcid.org/0000-0002-0208-1401)
- Long‐Sheng Song (ORCID: https://orcid.org/0000-0002-6035-8106)
- Rui Ni (ORCID: https://orcid.org/0000-0001-6135-816X)
- Jianxiang Song (ORCID: https://orcid.org/0000-0003-4503-6464)
- Tianqing Peng (ORCID: https://orcid.org/0000-0002-5199-9016)
- Xiaoyun Ji (ORCID: https://orcid.org/0000-0002-0801-8825)
- Dong Zheng
- Zhifeng Dong
- Douglas L. Jones (ORCID: https://orcid.org/0000-0002-5577-0091)
- Yifan Huang (ORCID: https://orcid.org/0009-0006-2054-8569)
- Zijun Su
Institutions
- Western University (CA)
- University of Iowa (US)
- London Health Sciences Centre (CA)
- Soochow University (CN)
- Yancheng Third People's Hospital (CN)
- First Affiliated Hospital of Soochow University (CN)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- JACC Basic to Translational Science
- Published
- 2026-04-17
- DOI
- https://doi.org/10.1016/j.jacbts.2026.101534
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Heart and Stroke Foundation of Canada
- National Natural Science Foundation of China
- Natural Sciences and Engineering Research Council of Canada
- National Heart, Lung, and Blood Institute