Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility
Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility
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KLHL24 泛素连接酶的稳定突变会导致角蛋白 14 丢失和人类皮肤脆弱。
DOI：
10.1038/ng.3701
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发表时间：
2016-12-01
期刊：
影响因子：
30.8
通讯作者：
Tang, Xu
中科院分区：
文献类型：
--
作者：
Lin, Zhimiao;Li, Shuo;Tang, Xu
皮肤完整性对于保护免受外部压力和创伤至关重要。角蛋白等结构蛋白的缺陷会导致皮肤脆弱，表现为大疱性表皮病（EB），这是一种危及生命的疾病。在这里，我们表明，显性突变KLHL 24，编码cullin 3-RBX 1泛素连接酶底物受体，导致EB。我们在5例EB患者中发现了KLHL 24基因的起始密码子突变。这些突变导致截短的KLHL 24蛋白缺少最初的28个氨基酸（KLHL 24-Delta N28）。KLHL 24-Delta N28比其野生型对应物更稳定，这是由于消除了autoubiquitination。我们进一步鉴定了角蛋白14（KRT 14）作为KLHL 24底物，并发现KLHL 24-Delta N28诱导KRT 14的过度泛素化和降解。使用敲入小鼠模型，我们已经证实K1 h124突变导致稳定的K1 h124-Delta N28并导致Krt 14降解。我们的研究结果确定了一个新的致病机制，由于autoubiquitination失调，并为相关疾病的治疗开辟了新的途径。
Skin integrity is essential for protection from external stress and trauma. Defects in structural proteins such as keratins cause skin fragility, epitomized by epidermolysis bullosa (EB), a life-threatening disorder. Here we show that dominant mutations of KLHL24, encoding a cullin 3-RBX1 ubiquitin ligase substrate receptor, cause EB. We have identified start-codon mutations in the KLHL24 gene in five patients with EB. These mutations lead to truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-Delta N28). KLHL24-Delta N28 is more stable than its wild-type counterpart owing to abolished autoubiquitination. We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-Delta N28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, we have confirmed that the K1h124 mutations lead to stabilized K1h124-Delta N28 and cause Krt14 degradation. Our findings identify a new disease-causing mechanism due to dysregulation of autoubiquitination and open new avenues for the treatment of related disorders.