title: Regulation of ENaC biogenesis by the stress response protein SERP1.
abstract: Cystic fibrosis lung disease is caused by reduced Cl(-) secretion along with enhanced Na(+) absorption, leading to reduced airway surface liquid and compromised mucociliary clearance. Therapeutic strategies have been developed to activate cystic fibrosis transmembrane conductance regulator (CFTR) or to overcome enhanced Na(+) absorption by the epithelial Na(+) channel (ENaC). In a split-ubiquitin-based two-hybrid screening, we identified stress-associated ER protein 1 (SERP1)/ribosome-associated membrane protein 4 as a novel interacting partner for the ENaC β-subunit. SERP1 is induced during cell stress and interacts with the molecular chaperone calnexin, thus controlling early biogenesis of membrane proteins. ENaC activity was measured in the human airway epithelial cell lines H441 and A549 and in voltage clamp experiments with ENaC-overexpressing Xenopus oocytes. We found that expression of SERP1 strongly inhibits amiloride-sensitive Na(+) transport. SERP1 coimmunoprecipitated and colocalized with βENaC in the endoplasmic reticulum, together with the chaperone calnexin. In contrast to the inhibitory effects on ENaC, SERP1 appears to promote expression of CFTR. Taken together, SERP1 is a novel cochaperone and regulator of ENaC expression.
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Faria
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lentze
authors.forename: Joana
authors.initials: J
authors.lastname: Almaça
authors.forename: Simão
authors.initials: S
authors.lastname: Luz
authors.forename: Luisa
authors.initials: L
authors.lastname: Alessio
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Tian
authors.forename: José Paulo
authors.initials: JP
authors.lastname: Martins
authors.forename: Pedro
authors.initials: P
authors.lastname: Cruz
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Mandana
authors.initials: M
authors.lastname: Rezwan
authors.forename: Carlos Miguel
authors.initials: CM
authors.lastname: Farinha
authors.forename: Daniel
authors.initials: D
authors.lastname: Auerbach
authors.forename: Margarida D
authors.initials: MD
authors.lastname: Amaral
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D000818:Animals; D037281:Calnexin / Q000378:metabolism; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; C575068:SERP1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D037281:Calnexin