Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1
Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1
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DOI：
10.1073/pnas.1313753110
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发表时间：
2013-12-10
影响因子：
11.1
通讯作者：
Berndt, Carsten
中科院分区：
文献类型：
--
作者：
Brautigam, Lars;Jensen, Lasse Dahl Ejby;Berndt, Carsten
胚胎发育依赖于复杂和精确协调的信号通路，包括特定的还原/氧化级联反应。硫氧还蛋白家族的氧化还原酶是通过蛋白质巯基的可逆翻译后修饰传递氧化还原信号的关键参与者。这个蛋白质家族在胚胎发育过程中的重要性最近已经被证明为谷氧还蛋白2，一种脊椎动物特异性谷胱甘肽-二硫键氧化还原酶，对胚胎脑发育具有关键作用。在这里，我们发现了谷氧还蛋白2在血管发育过程中的重要功能。基于双光子显微镜的共聚焦显微镜和延时研究表明，斑马鱼（一种研究脊椎动物胚胎发生的模式生物）中基于吗啉的谷氧还蛋白2敲低导致血管网络延迟和紊乱。我们能够证明，功能性血管系统的形成需要NAD（+）依赖性蛋白脱乙酰酶sirtuin 1的谷氧还蛋白2依赖性可逆S-谷胱甘肽化。使用质谱，我们确定了半胱氨酸残基的沉默调节蛋白1的保守催化区域作为目标的谷氧还蛋白2特异性去谷胱甘肽化。因此，谷氧还蛋白2介导的氧化还原调节控制sirtuin 1的酶活性，我们发现这是一种在斑马鱼和人类之间保守的机制。这些结果将S-谷胱甘肽化与脊椎动物发育和成功的胚胎血管生成联系起来。
Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified for glutaredoxin 2, a vertebrate-specific glutathione-disulfide oxidoreductase with a critical role for embryonic brain development. Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD(+)-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.