The Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel Requires a Unique Complement of Molecular Chaperones

被引:77
作者
Buck, Teresa M. [1 ]
Kolb, Alexander R. [1 ]
Boyd, Cary R. [2 ]
Kleyman, Thomas R. [2 ]
Brodsky, Jeffrey L. [1 ]
机构
[1] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15261 USA
基金
美国国家卫生研究院;
关键词
TRANSMEMBRANE CONDUCTANCE REGULATOR; ER-ASSOCIATED DEGRADATION; PROTEIN-DEGRADATION; NA+ CHANNEL; DNAJ HOMOLOG; MISFOLDED GLYCOPROTEINS; MEMBRANE TOPOLOGY; UBIQUITIN-LIGASE; QUALITY-CONTROL; CO-CHAPERONE;
D O I
10.1091/mbc.E09-11-0944
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The epithelial sodium channel (ENaC) is composed of a single copy of an alpha-, beta-, and gamma-subunit and plays an essential role in water and salt balance. Because ENaC assembles inefficiently after its insertion into the ER, a substantial percentage of each subunit is targeted for ER-associated degradation (ERAD). To define how the ENaC subunits are selected for degradation, we developed novel yeast expression systems for each ENaC subunit. Data from this analysis suggested that ENaC subunits display folding defects in more than one compartment and that subunit turnover might require a unique group of factors. Consistent with this hypothesis, yeast lacking the lumenal Hsp40s, Jem1 and Scj1, exhibited defects in ENaC degradation, whereas BiP function was dispensable. We also discovered that Jem1 and Scj1 assist in ENaC ubiquitination, and overexpression of ERdj3 and ERdj4, two lumenal mammalian Hsp40s, increased the proteasome-mediated degradation of ENaC in vertebrate cells. Our data indicate that Hsp40s can act independently of Hsp70 to select substrates for ERAD.
引用
收藏
页码:1047 / 1058
页数:12
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