ArticleThe Journal of biological chemistry2013
The Lhs1/GRP170 chaperones facilitate the endoplasmic reticulum-associated degradation of the epithelial sodium channel.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 57 citations in OpenAlex.
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- The scaffold protein IQGAP1 regulates the epithelial NaThe Journal of biological chemistry · 2025Article
- Thyroidal expression of ER molecular chaperone GRP170 is required for efficient TSH-mediated thyroid hormone synthesis.JCI insight · 2025Article
- Excess dietary sodium restores electrolyte and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron.American journal of physiology. Renal physiology · 2025Article
- The Essential Functions of Molecular Chaperones and Folding Enzymes in Maintaining Endoplasmic Reticulum Homeostasis.Journal of molecular biology · 2024Review
- Upregulation of α-ENaC induces pancreatic β-cell dysfunction, ER stress, and SIRT2 degradation.Journal of biomedical research · 2024Article
- Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum function.Molecular biology of the cell · 2024Article
- The expression system influences stability, maturation efficiency, and oligomeric properties of the potassium-chloride co-transporter KCC2.Neurochemistry international · 2024Article
- Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron.bioRxiv : the preprint server for biology · 2024Article
- Lhs1 dependent ERAD is determined by transmembrane domain context.The Biochemical journal · 2023Article
- Reshaping endoplasmic reticulum quality control through the unfolded protein response.Molecular cell · 2022Review
- The molecular chaperone GRP170 protects against ER stress and acute kidney injury in mice.JCI insight · 2022Article
- Paraoxonase 2 is an ER chaperone that regulates the epithelial NaAmerican journal of physiology. Cell physiology · 2022Article
- SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain.The Biochemical journal · 2021Article
- Paraoxonase 3 functions as a chaperone to decrease functional expression of the epithelial sodium channel.The Journal of biological chemistry · 2020Article
- The molecular basis of chaperone-mediated interleukin 23 assembly control.Nature communications · 2019Article
- The endoplasmic reticulum chaperone PfGRP170 is essential for asexual development and is linked to stress response in malaria parasites.Cellular microbiology · 2019Article
- Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.Cold Spring Harbor perspectives in biology · 2019Review
- Thumb domains of the three epithelial NaThe Journal of biological chemistry · 2018Article
- Understanding the role of glucose regulated protein 170 (GRP170) as a nucleotide exchange factor through molecular simulations.Journal of molecular graphics & modelling · 2018Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The epithelial sodium channel, ENaC, plays a critical role in maintaining salt and water homeostasis, and not surprisingly defects in ENaC function are associated with disease. Like many other membrane-spanning proteins, this trimeric protein complex folds and assembles inefficiently in the endoplasmic reticulum (ER), which results in a substantial percentage of the channel being targeted for ER-associated degradation (ERAD). Because the spectrum of factors that facilitates the degradation of ENaC is incomplete, we developed yeast expression systems for each ENaC subunit. We discovered that a conserved Hsp70-like chaperone, Lhs1, is required for maximal turnover of the ENaC α subunit. By expressing Lhs1 ATP binding mutants, we also found that the nucleotide exchange properties of this chaperone are dispensable for ENaC degradation. Consistent with the precipitation of an Lhs1-αENaC complex, Lhs1 holdase activity was instead most likely required to support the ERAD of αENaC. Moreover, a complex containing the mammalian Lhs1 homolog GRP170 and αENaC co-precipitated, and GRP170 also facilitated ENaC degradation in human, HEK293 cells, and in a Xenopus oocyte expression system. In both yeast and higher cell types, the effect of Lhs1 on the ERAD of αENaC was selective for the unglycosylated form of the protein. These data establish the first evidence that Lhs1/Grp170 chaperones can act as mediators of ERAD substrate selection.
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