HIF and HOIL-1L–mediated PKCζ degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury

• DOI: 10.1073/pnas.1713563114
• Publication Date: 2017-11-06T20:20:59Z
• Authors: Natalia D. Magnani; Laura A. Dada; Markus A. Queisser; Patricia L. Brazee; Lynn C. Welch; Kishore R. Anekalla; Guofei Zhou; Olga Vagin; Alexander V. Mish...; G. R. Scott Budinger; Kazuhiro Iwai; Aaron J. Ciechanover; Jacob I. Sznajder
• Keywords: Male; Mice, Knockout; Mice, Inbred ICR; 0303 health sciences; Cell Membrane; Down-Regulation; Apoptosis; Epithelial Cells; Lung Injury; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Endocytosis; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; A549 Cells; COS Cells; Chlorocebus aethiops; Animals; Humans; Carrier Proteins; Hypoxia

Significance

Exposure to hypoxia requires adaptive mechanisms for survival. During acute hypoxia, Na,K-ATPase endocytosis in alveolar epithelial cells occurs via protein kinase C zeta (PKCζ) phosphorylation of α 1 -Na,K-ATPase independently of the hypoxia-inducible factor (HIF). However, exaggerated Na,K-ATPase down-regulation leads to cell death. Here we report that during prolonged hypoxia plasma membrane Na,K-ATPase levels were maintained at ∼50% of normoxic values due to HIF-mediated up-regulation of HOIL-1L, which targets PKCζ for degradation. Silencing HOIL-1L in the lung epithelium prevented PKCζ degradation, causing Na,K-ATPase downregulation. Accordingly, HIF regulation of HOIL-1L targets the phosphorylated PKCζ for degradation and serves as an hypoxia-adaptive mechanism to stabilize the Na,K-ATPase, avoiding significant lung injury.