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

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Elevated CO2 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 CO2 signaling in mammalian alveolar epithelial cells as well as in diptera, nematodes and rodent lungs. In alveolar epithelial cells, elevated CO2 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 CO2 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 CO2-induced downregulation of Na,K-ATPase in Drosophila S2 cells. The importance and specificity of JNK CO2 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 CO2 signaling in mammals, diptera and nematodes.

Original languageEnglish (US)
Article numbere46696
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 8 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Evolutionary Conserved Role of c-Jun-N-Terminal Kinase in CO<sub>2</sub>-Induced Epithelial Dysfunction'. Together they form a unique fingerprint.

Cite this