Hypercapnia Induces Inositol-Requiring Enzyme 1α–Driven Endoplasmic Reticulum–associated Degradation of the Na,K-ATPase β-Subunit

• DOI: 10.1165/rcmb.2021-0114oc
• Publication Date: 2021-06-30T22:31:32Z
• Authors: Vitalii Kryvenko; Miriam Wessendorf; Khodr Tello; Susanne Herold; Rory E. Morty; Werner Seeger; István Vadász
• Keywords: 0301 basic medicine; Endoplasmic Reticulum-Associated Degradation; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; 3. Good health; Hypercapnia; Mice; 03 medical and health sciences; A549 Cells; Endoribonucleases; Animals; Humans; Sodium-Potassium-Exchanging ATPase

Acute respiratory distress syndrome is often associated with elevated levels of CO2 (hypercapnia) and impaired alveolar fluid clearance. Misfolding the Na,K-ATPase (NKA), a key molecule involved in both epithelial barrier tightness resolution edema, endoplasmic reticulum (ER) may decrease plasma membrane abundance transporter. Here, we investigated how hypercapnia affects NKA β-subunit (NKA-β) ER. Exposing murine precision-cut lung slices human A549 cells to led rapid NKA-β ER at cell surface. Knockdown mannosidase α class 1B member 1 degradation-enhancing α-mannosidase like protein by siRNA or treatment inhibitor kifunensine rescued loss ER, suggesting ER-associated degradation (ERAD) enzyme. Furthermore, activated unfolded response promoting phosphorylation inositol-requiring enzyme 1α (IRE1α), an against IRE1α prevented Of note, hypercapnia-induced was triggered Ca2+-dependent mechanism. In addition, inhibition inositol trisphosphate receptor decreased cells, that Ca2+ efflux from might be responsible for activation ERAD NKA-β. conclusion, here provide evidence attenuates maturation regulatory subunit activating ERAD, which contribute integrity patients acute hypercapnia.