机构：[1]State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.[2]Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China.[3]Institute of Molecular Medicine, Peking University, Beijing, China.[4]Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China.[5]Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.[6]Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.[7]National Center for Protein Sciences (Beijing), State Key Laboratory of Proteomics, Institute of Lifeomics, Beijing, China.[8]Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China.临床科室心脏内科中心首都医科大学附属安贞医院[9]Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.首都医科大学附属安贞医院[10]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its delta isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive. Here, we show that CaMKII-delta 9, the most abundant CaMKII-delta splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-delta 9, but not the previously well-studied CaMKII-delta 2 and CaMKII-delta 3, targets the ubiquitin-conjugating enzyme E2T (UBE2T) for phosphorylation and degradation, disrupting UBE2T-dependent DNA repair and leading to the accumulation of DNA damage and genome instability. These findings not only reveal a crucial role of CaMKII in the regulation of DNA repair, but also mark the CaMKII-delta 9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.
基金：
National Key R&D Program of China [2018YFA0800501, 2018YFA0507603]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [31671177, 81630008, 81790621, 31521062, 81370234]; Beijing Municipal Science & Technology CommissionBeijing Municipal Science & Technology Commission [Z171100000417006]; Beijing Natural Science FoundationBeijing Natural Science Foundation [5182010]
生物