Evolutionary Conserved Role of c-Jun-N-Terminal Kinase in CO2-Induced Epithelial Dysfunction

• DOI: 10.1371/journal.pone.0046696
• Publication Date: 2012-10-08T21:12:23Z
• Authors: István Vadász; Laura A. Dada; Arturo Briva; Iiro Taneli Helenius; Kfir Sharabi; Lynn C. Welch; Aileen M. Kelly; Benno A. Grzesik; G. R. Scott Budinger; Jing Liu; Werner Seeger; Greg J. Beitel; Yosef Gruenbaum; Jacob I. Sznajder
• Keywords: 0301 basic medicine; Science; Q; R; JNK Mitogen-Activated Protein Kinases; Epithelial Cells; Carbon Dioxide; Burkitt Lymphoma; Rats; Enzyme Activation; Evolution, Molecular; Pulmonary Alveoli; 03 medical and health sciences; Medicine; Animals; Humans; Drosophila; Phosphorylation; Sodium-Potassium-Exchanging ATPase; Caenorhabditis elegans; Protein Kinase C; Research Article

Elevated CO(2) levels (hypercapnia) occur in patients with respiratory diseases and impair alveolar epithelial integrity, in part, by inhibiting Na,K-ATPase function. Here, we examined the role of c-Jun N-terminal kinase (JNK) in CO(2) signaling in mammalian alveolar epithelial cells as well as in diptera, nematodes and rodent lungs. In alveolar epithelial cells, elevated CO(2) levels rapidly induced activation of JNK leading to downregulation of Na,K-ATPase and alveolar epithelial dysfunction. Hypercapnia-induced activation of JNK required AMP-activated protein kinase (AMPK) and protein kinase C-ζ leading to subsequent phosphorylation of JNK at Ser-129. Importantly, elevated CO(2) levels also caused a rapid and prominent activation of JNK in Drosophila S2 cells and in C. elegans. Paralleling the results with mammalian epithelial cells, RNAi against Drosophila JNK fully prevented CO(2)-induced downregulation of Na,K-ATPase in Drosophila S2 cells. The importance and specificity of JNK CO(2) signaling was additionally demonstrated by the ability of mutations in the C. elegans JNK homologs, jnk-1 and kgb-2 to partially rescue the hypercapnia-induced fertility defects but not the pharyngeal pumping defects. Together, these data provide evidence that deleterious effects of hypercapnia are mediated by JNK which plays an evolutionary conserved, specific role in CO(2) signaling in mammals, diptera and nematodes.