Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L

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• 作者：Naomi Araki ; Tomoaki Ishigami ; Hisako Ushio ; Shintaro Minegishi ; Masanari Umemura ; Yohei Miyagi ; Ichiro Aoki ; Hiroko Morinaga ; Koichi Tamura ; Yoshiyuki Toya ; Kazuaki Uchino ; Satoshi Umemura
• 关键词：Nedd4L ; ENaC ; Hypertension ; C2 domain ; Urinary tubules
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：16 October 2009
• 年：2009
• 卷：388
• 期：2
• 页码：290-296
• 全文大小：632 K

文摘

Epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH₂ terminal of the protein for subsequent degradation. One of the isoforms of human Nedd4L with evolutionarily new C2 domain was reported to play a significant role for degradating cell surface ENaC with interfering with wild isoforms by us previously. We focused the current analyses on isolating the binding molecules with C2 domain using yeast two-hybrid screening to elucidate further molecular interactions between ENaC and Nedd4L. We found NPC2, also known as HE-1, bind C2 domain of human Nedd4L and express along ASDN colocalized with Nedd4L. Additionally, in experiments using a model of salt-sensitive hypertension in Dahl rats, we provided evidence suggesting that transcriptional regulation and activation of NPC2 protein depends on sodium intake. NPC2 might regulate sodium reabsorption in the terminal nephron by interacting with ENaC–Nedd4L system.