title: Regulation of Na,K-ATPase during acute lung injury.
abstract: A hallmark of acute lung injury is the accumulation of a protein rich edema which impairs gas exchange and leads to hypoxemia. The resolution of lung edema is effected by active sodium transport, mostly contributed by apical Na(+) channels and the basolateral located Na,K-ATPase. It has been reported that the decrease of Na,K-ATPase function seen during lung injury is due to its endocytosis from the cell plasma membrane into intracellular pools. In alveolar epithelial cells exposed to severe hypoxia, we have reported that increased production of mitochondrial reactive oxygen species leads to Na,K-ATPase endocytosis and degradation. We found that this regulated process follows what is referred as the Phosphorylation-Ubiquitination-Recognition-Endocytosis-Degradation (PURED) pathway. Cells exposed to hypoxia generate reactive oxygen species which activate PKC zeta which in turn phosphorylates the Na,K-ATPase at the Ser18 residue in the N-terminus of the alpha1-subunit leading the ubiquitination of any of the four lysines (K16, K17, K19, K20) adjacent to the Ser18 residue. This process promotes the alpha1-subunit recognition by the mu2 subunit of the adaptor protein-2 and its endocytosis trough a clathrin dependent mechanism. Finally, the ubiquitinated Na,K-ATPase undergoes degradation via a lysosome/proteasome dependent mechanism.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Emilia
authors.initials: E
authors.lastname: Lecuona
authors.forename: Humberto E
authors.initials: HE
authors.lastname: Trejo
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004705:Endocytosis; D006801:Humans; D010766:Phosphorylation; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase