MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
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DOI：
10.1172/jci133181
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发表时间：
2020-09-01
影响因子：
15.9
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
--
作者：
Konstantinidis, Klitos;Bezzerides, Vassilios J.;Anderson, Mark E.
氧化应激可导致健康和疾病。在这里，我们表明，无脊椎动物和脊椎动物共享一个共同的立体特异性氧化还原途径，保护对应激的病理反应，在降低生理性能的成本，通过限制Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）的活动。MICAL 1是一种被认为专门靶向肌动蛋白的甲硫氨酸单加氧酶，MSRB是一种甲硫氨酸还原酶，它们控制着M308的立体特异性氧化还原状态，M308是CaMKII钙调蛋白结合（CaM结合）结构域中的一个高度保守的残基。氧化的或突变的M308（M308 V）降低CaM结合和CaMK II活性，而小鼠中MICAL 1的缺乏引起心律失常和由于CaMK II过度激活而过早死亡。模拟M308氧化的作用降低了小鼠的战斗或逃跑反应，显著损害了果蝇的心脏功能，并在人诱导多能干细胞衍生的心肌细胞中引起了疾病保护，其中儿茶酚胺能多态性室性心动过速是一种CaMK II敏感的遗传性心律失常综合征。我们的研究确定了一个立体特异性的氧化还原途径，调节心脏的生理和病理反应，跨物种的压力。
Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.