Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC
Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC
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DOI：
10.1242/jcs.198242
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发表时间：
2017-03
影响因子：
4
通讯作者：
Hui You;Yamei Ge;Jian Zhang;Yizhi Cao;Jing Xing;D. Su;Yujie Huang;Min Li;Shen Qu;F. Sun;Xiubin Liang
中科院分区：
文献类型：
--
作者：
Hui You;Yamei Ge;Jian Zhang;Yizhi Cao;Jing Xing;D. Su;Yujie Huang;Min Li;Shen Qu;F. Sun;Xiubin Liang
上皮Na+通道泛素化（ENaC）在细胞功能中起着重要作用，包括Na+跨膜转运、Na+和水平衡以及血压稳定。已发表的研究表明，ENaC亚基是酵母系统中ER相关降解（ERAD）的靶标。然而，蛋白酶体介导的ENaC亚基降解的分子机制仍有待建立。Derlin-1是一种E3连接酶介导剂，将公认的靶蛋白与细胞溶质中泛素介导的蛋白酶体降解联系起来。在本研究中，我们发现derlin-1在蛋白水平上抑制ENaC的表达，α-ENaC亚基（也称为SCNN 1A）在膜锚定结构域或环区与derlin-1发生物理相互作用，derlin-1启动α-ENaC的逆转录转运。此外，HUWE 1，一种内质网（ER）驻留的E3泛素连接酶，被募集并促进α-ENaC的K11连接的多泛素化，从而形成α-ENaC泛素介导的降解复合物。这些发现表明derlin-1促进ENaC泛素化并增强ENaC泛素介导的蛋白酶体降解。因此，derlin-1通路可能代表哺乳动物细胞中ENaC识别和降解的重要早期检查点。Derlin-1与ENaC结合，并通过ER相关降解促进其泛素化和降解。E3连接酶HUWE 1是必需的，并将K11连接的泛素链添加到ENaC，促进其降解。
ABSTRACT Ubiquitylation of the epithelial Na+ channel (ENaC) plays a critical role in cellular functions, including transmembrane transport of Na+, Na+ and water balance, and blood pressure stabilization. Published studies have suggested that ENaC subunits are targets of ER-related degradation (ERAD) in yeast systems. However, the molecular mechanism underlying proteasome-mediated degradation of ENaC subunits remains to be established. Derlin-1, an E3 ligase mediator, links recognized target proteins to ubiquitin-mediated proteasomal degradation in the cytosol. In the present study, we found that derlin-1 suppressed the expression of ENaC at the protein level and that the subunit α-ENaC (also known as SCNN1A) physically interacted with derlin-1 at the membrane-anchored domains or the loop regions, and that derlin-1 initiated α-ENaC retrotranslocation. In addition, HUWE1, an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase, was recruited and promoted K11-linked polyubiquitylation of α-ENaC and, hence, formation of an α-ENaC ubiquitin-mediated degradation complex. These findings suggest that derlin-1 promotes ENaC ubiquitylation and enhances ENaC ubiquitin- mediated proteasome degradation. The derlin-1 pathway therefore may represent a significant early checkpoint in the recognition and degradation of ENaC in mammalian cells. Summary: Derlin-1 binds to ENaC and promotes its ubiquitylation and degradation via ER-related degradation. The E3 ligase HUWE1 is required and adds K11-linked ubiquitin chains to ENaC prompting its degradation.