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  Hypercapnia Induces Inositol-Requiring Enzyme 1 alpha-Driven Endoplasmic Reticulum-associated Degradation of the Na,K-ATPase beta-Subunit

Kryvenko, V., Wessendorf, M., Tello, K., Herold, S., Morty, R. E., Seeger, W., et al. (2021). Hypercapnia Induces Inositol-Requiring Enzyme 1 alpha-Driven Endoplasmic Reticulum-associated Degradation of the Na,K-ATPase beta-Subunit. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 65(6), 615-629. doi:10.1165/rcmb.2021-0114OC.

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Kryvenko, Vitalii, Author
Wessendorf, Miriam, Author
Tello, Khodr, Author
Herold, Susanne1, Author              
Morty, Rory E.1, Author              
Seeger, Werner1, 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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 Abstract: Acute respiratory distress syndrome is often associated with elevated levels of CO2 (hypercapnia) and impaired alveolar fluid clearance. Misfolding of the Na,K-ATPase (NKA), a key molecule involved in both alveolar epithelial barrier tightness and resolution of alveolar edema, in the endoplasmic reticulum (ER) may decrease plasma membrane abundance of the transporter. Here, we investigated how hypercapnia affects the NKA beta-subunit (NKA-beta) in the ER. Exposing murine precision-cut lung slices and human alveolar epithelial A549 cells to elevated CO2 levels led to a rapid decrease of NKA-beta abundance in the ER and at the cell surface. Knockdown of ER mannosidase alpha class 1B member 1 and ER degradationenhancing alpha-mannosidase like protein 1 by siRNA or treatment with the mannosidase alpha class 1B member 1 inhibitor kifunensine rescued loss of NKA-beta in the ER, suggesting ER-associated degradation (ERAD) of the enzyme. Furthermore, hypercapnia activated the unfolded protein response by promoting phosphorylation of inositol-requiring enzyme 1 alpha (IRE1 alpha), and treatment with an siRNA against IRE1 alpha prevented the decrease of NKA-beta in the ER. Of note, the hypercapnia-induced phosphorylation of IRE1 alpha was triggered by a Ca2+-dependent mechanism. In addition, inhibition of the inositol trisphosphate receptor decreased phosphorylation levels of IRE1 alpha in precision-cut lung slices and A549 cells, suggesting that Ca2+ efflux from the ER might be responsible for IRE1 alpha activation and ERAD of NKA-beta. In conclusion, here we provide evidence that hypercapnia attenuates maturation of the regulatory subunit of NKA by activating IRE1 alpha and promoting ERAD, which may contribute to impaired alveolar epithelial integrity in patients with acute respiratory distress syndrome and hypercapnia.

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 Dates: 2021-06-302021-12
 Publication Status: Published in print
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 Identifiers: ISI: 000726579100009
DOI: 10.1165/rcmb.2021-0114OC
PMID: 34192507
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Title: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Source Genre: Journal
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Pages: - Volume / Issue: 65 (6) Sequence Number: - Start / End Page: 615 - 629 Identifier: ISSN: 1044-1549