State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, China.
Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
Nat Cell Biol. 2019 Sep;21(9):1152-1163. doi: 10.1038/s41556-019-0380-8. Epub 2019 Sep 2.
Ca/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ 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-δ9, the most abundant CaMKII-δ splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-δ9, but not the previously well-studied CaMKII-δ2 and CaMKII-δ3, 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-δ9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.
钙/钙调蛋白依赖性激酶 II（CaMKII）是一种多功能丝氨酸/苏氨酸激酶家族，其 δ 同工型在心脏中占优势。CaMKII 的过度激活在严重心脏疾病的发病机制中起着关键作用，包括心肌梗死、心肌病和心力衰竭。然而，CaMKII 剪接变异体的身份以及 CaMKII 介导的心脏病理学的机制仍不清楚。在这里，我们表明 CaMKII-δ9，人类心脏中最丰富的 CaMKII-δ 剪接变异体，通过破坏心肌细胞基因组稳定性，强烈促进心肌细胞死亡、心肌病和心力衰竭。在机制上，CaMKII-δ9 而不是以前研究充分的 CaMKII-δ2 和 CaMKII-δ3，靶向泛素缀合酶 E2T（UBE2T）进行磷酸化和降解，破坏 UBE2T 依赖性 DNA 修复，导致 DNA 损伤和基因组不稳定性的积累。这些发现不仅揭示了 CaMKII 在调节 DNA 修复中的关键作用，而且还将 CaMKII-δ9-UBE2T-DNA 损伤途径标记为心肌病和心力衰竭的重要治疗靶点。
