The formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases (PADs), including PAD1-4. Its physiological role is largely unknown. By using an unbiased proteomic approach of lung tissues, we discovered that FBLN5 and LTBP4, two key elastogenic proteins, were temporally modified in mouse and human lungs. We further demonstrated that PAD2 citrullinated FBLN5 preferentially in young lungs compared to adult lungs. Genetic ablation of PAD2 resulted in attenuated elastogenesis in vitro and age-dependent emphysema in vivo. Mechanistically, citrullination protected FBLN5 from proteolysis and subsequent inactivation of its elastogenic activity. Furthermore, citrullinated but not native FBLN5 partially rescued in vitro elastogenesis in the absence of PAD activity. Our data uncover a novel function of citrullination, namely promoting elastogenesis, and provide additional insights to how elastogenesis is regulated.

弹性纤维的形成仅在围产期活跃。弹性发生如何在发育上受到调节尚不完全清楚。瓜氨酸化是一种独特的翻译后修饰形式，由肽基精氨酸脱亚胺酶 (PAD) 催化，包括 PAD1-4。它的生理作用在很大程度上是未知的。通过使用肺组织的无偏蛋白质组学方法，我们发现 FBLN5 和 LTBP4 这两种关键的弹性蛋白在小鼠和人肺中被暂时修饰。我们进一步证明，与成人肺相比，PAD2 瓜氨酸 FBLN5 在年轻肺中优先出现。PAD2 的基因消融导致体外弹性发生减弱和体内年龄依赖性肺气肿. 从机制上讲，瓜氨酸化保护 FBLN5 免受蛋白水解和随后的弹性活性失活。此外，瓜氨酸化但非天然 FBLN5在没有 PAD 活性的情况下部分挽救了体外弹性发生。我们的数据揭示了瓜氨酸化的一种新功能，即促进弹性生成，并为弹性生成的调节方式提供了额外的见解。