The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice
The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice
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DOI：
10.1038/ng0298-143
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发表时间：
1998-02-01
期刊：
影响因子：
30.8
通讯作者：
Copeland, NG
中科院分区：
文献类型：
--
作者：
Perry, WL;Hustad, CM;Copeland, NG
非聚集致死性18 H（a（18 H））小鼠是黑色聚集，具有黑色耳廓毛。这些小鼠的独特之处在于，它们会产生一系列免疫性疾病，这些疾病在其他agglutinin突变小鼠中未见（1）。在JU/Ct背景下，a（18 H）小鼠发生大肠炎性疾病。在C57 BL/6 J背景下，它们发生致命疾病，其特征在于肺部慢性间质性炎症和肺泡蛋白沉积症、腺胃和皮肤炎症，导致由于持续瘙痒引起的瘢痕形成，以及淋巴细胞、造血细胞和前胃上皮细胞增生。先前的研究表明，a（18 H）突变是由影响两个位点的旁着丝粒倒位引起的：agglutination和另一个尚未确定的位点，命名为Itch（临时基因符号为Itch），它负责a（18 H）小鼠的免疫表型（1）。在这里，我们证实，（18 H）的结果从一个倒位，并表明，痒编码一种新的E3泛素蛋白连接酶，蛋白参与泛素介导的蛋白质降解。我们的研究结果表明，泛素依赖的蛋白水解是体内免疫反应的重要介质，并提供证据痒的炎症和上皮细胞和造血细胞生长的调节中的作用。
Non-agouti-lethal 18H (a(18H)) mice are dark agouti with black pinna hairs. What makes these mice unique is that they develop a spectrum of immunological diseases not seen in other agouti mutant mice(1). On the JU/Ct background, a(18H) mice develop an inflammatory disease of the large intestine, On the C57BL/6J background, they develop a fatal disease characterized by pulmonary chronic interstitial inflammation and alveolar proteinosis, inflammation of the glandular stomach and skin resulting in scarring due to constant itching, and hyperplasia of lymphoid cells, haematopoietic cells and the forestomach epithelium. Previous studies suggested that the a(18H) mutation results from a paracentric inversion that affects two loci: agouti and another, as yet unidentified locus designated itchy (the provisional gene symbol is Itch), that is responsible for the immunological phenotype of a(18H) mice(1). Here we confirm that a(18H) results from an inversion and show that Itch encodes a novel E3 ubiquitin protein ligase, a protein involved in ubiquitin-mediated protein degradation. Our results indicate that ubiquitin-dependent proteolysis is an important mediator of the immune response in vivo and provide evidence for itch's role in inflammation and the regulation of epithelial and haematopoietic cell growth.