CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair
CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair
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CaMKII-delta 9 通过破坏 UBE2T 依赖性 DNA 修复促进心肌病
DOI：
10.1038/s41556-019-0380-8
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发表时间：
2019-09-01
影响因子：
21.3
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
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作者：
Zhang, Mao;Gao, Hua;Xiao, Rui-Ping
CaMKII是一个多功能的丝氨酸/苏氨酸激酶家族，其β亚型在心脏中占主导地位。CaMKII的过度激活在包括心肌梗死、心肌病和心力衰竭在内的严重心脏疾病的发病机制中起着关键作用。然而，CaMKII剪接变异体的识别和CaMKII介导的心脏病理的潜在机制(S)仍然不清楚。在这里，我们发现CaMKII-delta9，人类心脏中含量最丰富的CaMKII-delta9剪接变体，通过破坏心肌细胞基因组的稳定性而有效地促进心肌细胞死亡、心肌病和心力衰竭。在机制上，CaMKII-delta9，而不是以前研究得很好的CaMKII-delta2和CaMKII-delta3，靶向于泛素结合酶E2T(UBE2T)进行磷酸化和降解，扰乱依赖UBE2T的DNA修复，导致DNA损伤的积累和基因组的不稳定。这些发现不仅揭示了CaMKII在DNA修复调节中的重要作用，而且标志着CaMKII-Delta 9-UBE2T-DNA损伤通路成为心肌病和心力衰竭的重要治疗靶点。
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.