Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

0301 basic medicine 0303 health sciences Lysine Tumor Suppressor Proteins Ubiquitin-Protein Ligases Cell Membrane Ubiquitination Membrane Proteins 15. Life on land Models, Biological 3. Good health Mice 03 medical and health sciences HEK293 Cells Protein Domains Proteolysis Animals Humans Epithelial Sodium Channels Polyubiquitin Protein Binding
DOI: 10.1242/jcs.198242 Publication Date: 2017-01-31T01:40:33Z
ABSTRACT
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.
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