Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071, USA.
Genus PLC, DeForest, WI 53532, USA.
Biol Reprod. 2022 Dec 10;107(6):1395-1410. doi: 10.1093/biolre/ioac173.
Citrullination, the post-translational modification of arginine residues, is catalyzed by the four catalytically active peptidylarginine deiminase (PAD or PADI) isozymes and alters charge to affect target protein structure and function. PADs were initially characterized in rodent uteri and, since then, have been described in other female tissues including ovaries, breast, and the lactotrope and gonadotrope cells of the anterior pituitary gland. In these tissues and cells, estrogen robustly stimulates PAD expression resulting in changes in levels over the course of the female reproductive cycle. The best-characterized targets for PADs are arginine residues in histone tails, which, when citrullinated, alter chromatin structure and gene expression. Methodological advances have allowed for the identification of tissue-specific citrullinomes, which reveal that PADs citrullinate a wide range of enzymes and structural proteins to alter cell function. In contrast to their important physiological roles, PADs and citrullinated proteins are also involved in several female-specific diseases including autoimmune disorders and reproductive cancers. Herein, we review current knowledge regarding PAD expression and function and highlight the role of protein citrullination in both normal female reproductive tissues and associated diseases.
瓜氨酸化，即精氨酸残基的翻译后修饰，由四个催化活性的肽基精氨酸脱亚氨酶（PAD 或 PADI）同工酶催化，改变电荷以影响靶蛋白的结构和功能。PAD 最初在啮齿动物的子宫中被描述，此后，在其他女性组织中也有描述，包括卵巢、乳房以及垂体前叶的催乳素细胞和促性腺激素细胞。在这些组织和细胞中，雌激素强烈刺激 PAD 的表达，导致其在女性生殖周期中水平发生变化。PAD 的最佳特征靶标是组蛋白尾部的精氨酸残基，当这些精氨酸残基发生瓜氨酸化时，会改变染色质结构和基因表达。方法学的进步使得能够鉴定组织特异性的瓜氨酸化组，这揭示了 PAD 可以瓜氨酸化广泛的酶和结构蛋白，从而改变细胞功能。与它们在生理上的重要作用相反，PAD 和瓜氨酸化蛋白也参与了几种女性特有的疾病，包括自身免疫性疾病和生殖系统癌症。本文综述了 PAD 表达和功能的最新知识，并强调了蛋白质瓜氨酸化在正常女性生殖组织和相关疾病中的作用。
