| First Author | Magnani ND | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 47 | Pages | E10178-E10186 |
| PubMed ID | 29109255 | Mgi Jnum | J:254318 |
| Mgi Id | MGI:6101223 | Doi | 10.1073/pnas.1713563114 |
| Citation | Magnani ND, et al. (2017) HIF and HOIL-1L-mediated PKCzeta degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury. Proc Natl Acad Sci U S A 114(47):E10178-E10186 |
| abstractText | Organisms have evolved adaptive mechanisms in response to stress for cellular survival. During acute hypoxic stress, cells down-regulate energy-consuming enzymes such as Na,K-ATPase. Within minutes of alveolar epithelial cell (AEC) exposure to hypoxia, protein kinase C zeta (PKCzeta) phosphorylates the alpha1-Na,K-ATPase subunit and triggers it for endocytosis, independently of the hypoxia-inducible factor (HIF). However, the Na,K-ATPase activity is essential for cell homeostasis. HIF induces the heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), which leads to PKCzeta degradation. Here we report a mechanism of prosurvival adaptation of AECs to prolonged hypoxia where PKCzeta degradation allows plasma membrane Na,K-ATPase stabilization at approximately 50% of normoxic levels, preventing its excessive down-regulation and cell death. Mice lacking HOIL-1L in lung epithelial cells (Cre(SPC)/HOIL-1L(fl/fl) ) were sensitized to hypoxia because they express higher levels of PKCzeta and, consequently, lower plasma membrane Na,K-ATPase levels, which increased cell death and worsened lung injury. In AECs, expression of an alpha1-Na,K-ATPase construct bearing an S18A (alpha1-S18A) mutation, which precludes PKCzeta phosphorylation, stabilized the Na,K-ATPase at the plasma membrane and prevented hypoxia-induced cell death even in the absence of HOIL-1L. Adenoviral overexpression of the alpha1-S18A mutant Na,K-ATPase in vivo rescued the enhanced sensitivity of Cre(SPC/)HOIL-1L(fl/fl) mice to hypoxic lung injury. These data suggest that stabilization of Na,K-ATPase during severe hypoxia is a HIF-dependent process involving PKCzeta degradation. Accordingly, we provide evidence of an important adaptive mechanism to severe hypoxia, whereby halting the exaggerated down-regulation of plasma membrane Na,K-ATPase prevents cell death and lung injury. |
