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  TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase beta-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia

Gabrielli, N. M., Mazzocchi, L. C., Kryvenko, V., Tello, K., Herold, S., Morty, R. E., et al. (2021). TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase beta-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 9: 689983. doi:10.3389/fcell.2021.689983.

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 Creators:
Gabrielli, Nieves M., Author
Mazzocchi, Luciana C., Author
Kryvenko, Vitalii, Author
Tello, Khodr, Author
Herold, Susanne1, Author              
Morty, Rory E.1, Author              
Grimminger, Friedrich, Author
Dada, Laura A., Author
Seeger, Werner1, Author              
Sznajder I, Jacob, Author
Vadasz, Istvan1, Author              
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: ACUTE LUNG INJURY; ENDOPLASMIC-RETICULUM; RECEPTOR ENDOCYTOSIS; MOLECULAR-WEIGHT; PLASMA-MEMBRANE; DOWN-REGULATION; DEGRADATION; CELLS; PROTEINS; ALPHACell Biology; Developmental Biology; Na; K-ATPase beta-subunit; carbon dioxide; ubiquitination; endocytosis; PKC-zeta; TRAF2; hypercapnia; adherens junction;
 Abstract: Several acute and chronic lung diseases are associated with alveolar hypoventilation leading to accumulation of CO2 (hypercapnia). The beta-subunit of the Na,K-ATPase plays a pivotal role in maintaining epithelial integrity by functioning as a cell adhesion molecule and regulating cell surface stability of the catalytic alpha-subunit of the transporter, thereby, maintaining optimal alveolar fluid balance. Here, we identified the E3 ubiquitin ligase for the Na, K-ATPase beta-subunit, which promoted polyubiquitination, subsequent endocytosis and proteasomal degradation of the protein upon exposure of alveolar epithelial cells to elevated CO2 levels, thus impairing alveolar integrity. Ubiquitination of the Na, K-ATPase beta-subunit required lysine 5 and 7 and mutating these residues (but not other lysines) prevented trafficking of Na,K-ATPase from the plasma membrane and stabilized the protein upon hypercapnia. Furthermore, ubiquitination of the Na, K-ATPase beta-subunit was dependent on prior phosphorylation at serine 11 by protein kinase C (PKC)-zeta. Using a protein microarray, we identified the tumor necrosis factor receptor-associated factor 2 (TRAF2) as the E3 ligase driving ubiquitination of the Na, K-ATPase beta-subunit upon hypercapnia. Of note, prevention of Na, K-ATPase beta-subunit ubiquitination was necessary and sufficient to restore the formation of cell-cell junctions under hypercapnic conditions. These results suggest that a hypercapnic environment in the lung may lead to persistent epithelial dysfunction in affected patients. As such, the identification of the E3 ligase for the Na, K-ATPase may provide a novel therapeutic target, to be employed in patients with acute or chronic hypercapnic respiratory failure, aiming to restore alveolar epithelial integrity.

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Language(s): eng - English
 Dates: 2021-07-02
 Publication Status: Published online
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000673990000001
DOI: 10.3389/fcell.2021.689983
PMID: 34277634
 Degree: -

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Title: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Source Genre: Journal
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Publ. Info: AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND : FRONTIERS MEDIA SA
Pages: - Volume / Issue: 9 Sequence Number: 689983 Start / End Page: - Identifier: ISSN: 2296-634X