The E3 ubiquitin ligase Itch controls the protein stability of p63
The E3 ubiquitin ligase Itch controls the protein stability of p63
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DOI：
10.1073/pnas.0603449103
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发表时间：
2006-08-22
影响因子：
11.1
通讯作者：
Melino, Gerry
中科院分区：
文献类型：
--
作者：
Rossi, Mario;Aqeilan, Rami I.;Melino, Gerry
p63是p53转录因子家族的一员，在上皮细胞发育中起重要作用，调节细胞周期和凋亡。尽管p63活性主要在翻译后水平上受到调节，但p63蛋白稳定性的控制还远未被完全理解。在这里，我们表明，Hect（同源的E6相关蛋白C末端）含有Nedd 4样泛素蛋白连接酶痒结合，泛素化，并促进p63的降解。物理相互作用发生在PY和SAM（无菌a基序）结构域之间的边界;单个Y504 F突变显著影响p63降解。瘙痒和p63在表皮和原代角质形成细胞中共表达，其中瘙痒控制p63蛋白稳态水平。因此，p63蛋白水平在Itch敲除角质形成细胞中显著增加。这些数据表明，瘙痒在控制内源性p63蛋白水平的机制中具有重要作用，因此有助于在生理条件下调节p63。
p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis. Even though p63 activity is regulated mainly at the posttranslational level, the control of p63 protein stability is far from being fully understood. Here, we show that the Hect (homologous to the E6-associated protein C terminus)-containing Nedd4-like ubiquitin protein ligase Itch binds, ubiquitylates, and promotes the degradation of p63. The physical interaction occurs at the border between the PY and the SAM (sterile a motif) domains; a single Y504F mutation significantly affects p63 degradation. Itch and p63 are coexpressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes. These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions.