Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity
Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity
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DOI：
10.1038/ng1493
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发表时间：
2005-01-01
期刊：
影响因子：
30.8
通讯作者：
Hovnanian, A
中科院分区：
文献类型：
--
作者：
Descargues, P;Deraison, C;Hovnanian, A
编码丝氨酸蛋白酶抑制剂lekti的SPINK5突变会导致Netherton综合征，一种严重的常染色体隐性遗传性皮肤病。Spink5(-/-)小鼠忠实地复制了Netherton综合征的主要特征，包括脱皮改变、角质化受损、毛发畸形和皮肤屏障缺陷。Lekti缺乏症是由于角质层胰酶和角质层乳糜酶样酶活性过强引起桥粒蛋白1的降解，从而导致上颗粒层桥粒的异常切割。这会导致角质层粘连缺陷，从而导致皮肤屏障功能的丧失。Profilaggrin处理增加，并暗示Lekti参与角化过程。这项工作确定Lekti是表皮蛋白酶活性的关键调节因子，桥粒芯糖蛋白1的降解是Netherton综合征的主要致病事件。
Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.