The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid.
The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid.
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DOI：
10.1038/ncb2134
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发表时间：
2011-01
影响因子：
21.3
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中科院分区：
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颅面异常（CFA）是最常见的人类先天性疾病，也是婴儿死亡和儿童发病的主要原因。尽管 CFA 似乎是由遗传因素和环境影响共同引起的，但大多数 CFA 的潜在基因缺陷和病理机制目前尚不清楚。在这里，我们揭示了 E3 泛素连接酶 Wwp2 在调节颅面图案中的未知作用。缺乏 Wwp2 的小鼠会出现颅面部区域畸形。 Wwp2 存在于软骨中，其表达受 Sox9 控制。我们的研究表明，Wwp2 通过与 Goosecoid (Gsc) 相互作用影响颅面图案，Goosecoid (Gsc) 是一种配对样同源框转录因子，在颅面发育中发挥重要作用。我们发现 Wwp2 相关的 Gsc 是关键软骨调节蛋白 Sox6 的转录激活因子。 Wwp2 与 Gsc 相互作用以促进其单泛素化，这是 Gsc 最佳转录激活所需的翻译后修饰。我们的结果确定了 Wwp2 在体内调节的第一个生理途径，并确定了 Wwp2 控制颅面发育的独特非蛋白水解机制。
Craniofacial anomalies (CFA) are the most frequent human congenital disease and a major cause of infant mortality and childhood morbidity. Although CFA appear to arise from a combination of genetic factors and environmental influences, the underlying gene defects and pathomechanisms for the majority of CFA are currently unknown. Here we reveal an unknown role for the E3 ubiquitin ligase Wwp2 in regulating craniofacial patterning. Mice deficient for Wwp2 develop malformations of the craniofacial region. Wwp2 is present in cartilage where its expression is controlled by Sox9. Our studies demonstrate that Wwp2 influences craniofacial patterning through its interactions with Goosecoid (Gsc), a paired-like homeobox transcription factor that plays an important role in craniofacial development. We show that Wwp2 associated Gsc is a transcriptional activator of the key cartilage regulatory protein Sox6. Wwp2 interacts with Gsc to facilitate its mono-ubiquitination, a post-translational modification required for optimal transcriptional activation of Gsc. Our results identify the first physiological pathway regulated by Wwp2 in vivo as well as identify a unique non-proteolytic mechanism through which the Wwp2 controls craniofacial development.