Validation of the Intermolecular Disulfide Bond in Caspase-2.
Validation of the Intermolecular Disulfide Bond in Caspase-2.
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作者：
Caspase-2 属于参与细胞死亡途径的蛋白质家族。涉及 caspase-2 的研究尚未对激活的 caspase-2 的上游激活信号或下游底物得出明确的结论。在这里，我们研究了 caspase-2 形成二硫键二聚体的独特且高度保守的能力。二硫键可以发挥结构作用，但它们也可以改变酶活性和蛋白质在细胞质内的定位。我们证明 caspase-2 必须首先二聚化才能形成二硫键。这一发现表明二硫键的形成是一种受调节的活化机制。我们还研究了各种刺激，其中一些先前已在 caspase-2 背景下发表，另一些则未在 caspase-2 缺陷细胞中进行。我们的结果显示 caspase-2 缺陷细胞对某些刺激有部分保护作用，但尚未发现真正的激活信号，其中 caspase-2 的缺失具有完全保护作用。半胱天冬酶是参与细胞死亡的蛋白质家族。尽管几个 caspase 成员已得到很好的表征，但 caspase-2 仍然是个谜。 Caspase-2 与多种表型有关，但该领域对其上游激活信号或其下游蛋白质靶标尚未达成共识。此外，caspase-2形成二硫键二聚体的独特能力尚未得到深入研究。在这里，我们研究了诱导二聚化背景下的二硫键，表明二硫键的形成是二聚化依赖性的。我们还探索和回顾了 caspase-2 领域发表的几种刺激，测试铁死亡诱导刺激，并研究体内感染模型。我们假设二硫键最终将被证明对于 caspase-2 的进化功能至关重要。要证明这一点，需要发现细胞死亡表型，其中 caspase-2 绝对是必需的。
Caspase-2 belongs to a family of proteins that are involved in cell death pathways. Studies involving caspase-2 have not led to a clear verdict on either the upstream activating signal or the downstream substrates of activated caspase-2. Here, we investigate the unique and highly conserved ability of caspase-2 to form a disulfide-bonded dimer. Disulfide bonds can serve structural roles, but they can also alter the enzymatic activity and localization of proteins within the cytosol. We show that caspase-2 must first dimerize for the disulfide bond to form. This finding suggests that disulfide bond formation is a regulated mechanism of activation. We also investigated various stimuli, some that have been previously published in the context of caspase-2 and some that have not, in caspase-2-deficient cells. Our results show partial protection in caspase-2-deficient cells for some of the stimuli, but a true activating signal, where the loss of caspase-2 is completely protective, has yet to be found. Caspases are a family of proteins involved in cell death. Although several caspase members have been well characterized, caspase-2 remains enigmatic. Caspase-2 has been implicated in several phenotypes, but there has been no consensus in the field about its upstream activating signals or its downstream protein targets. In addition, the unique ability of caspase-2 to form a disulfide-bonded dimer has not been studied in depth. Herein, we investigate the disulfide bond in the context of inducible dimerization, showing that disulfide bond formation is dimerization dependent. We also explore and review several stimuli published in the caspase-2 field, test ferroptosis-inducing stimuli, and study in vivo infection models. We hypothesize that the disulfide bond will ultimately prove to be essential for the evolved function of caspase-2. Proving this will require the discovery of cell death phenotypes where caspase-2 is definitively essential.
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影响因子：
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