Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling


Carbon dioxide (CO(2)) is increasingly being appreciated as an intracellular signaling molecule that affects inflammatory and immune responses. Elevated arterial CO(2) (hypercapnia) is encountered in a range of clinical conditions, including chronic obstructive pulmonary disease, and as a consequence of therapeutic ventilation in acute respiratory distress syndrome. In patients suffering from this syndrome, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis, which are associated with improved patient outcome. However, the molecular mechanisms underlying the beneficial effects of hypercapnia and the relative contribution of elevated CO(2) or associated acidosis to this response remain poorly understood. Recently, a role for the non-canonical NF-?B pathway has been postulated to be important in signaling the cellular transcriptional response to CO(2). In this study, we demonstrate that in cells exposed to elevated CO(2), the NF-?B family member RelB was cleaved to a lower molecular weight form and translocated to the nucleus in both mouse embryonic fibroblasts and human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlated with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing was sensitive to proteasomal inhibition by MG-132 but was independent of the activity of glycogen synthase kinase 3ß or MALT-1, both of which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO(2)-sensitive NF-?B family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.

Publication DOI: https://doi.org/10.1074/jbc.M112.347971
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences > Cellular and Molecular Biomedicine
Uncontrolled Keywords: animals,carbon dioxide,tumor cell line,cell nucleus,epithelial cells,fibroblasts,gene expression regulation,humans,hypercapnia,mice,biological models,RNA interference,signal transduction,transcription factor,RelB
Full Text Link: https://www.ncb ... les/PMC3340129/
Related URLs: http://www.jbc. ... nt/287/17/14004 (Publisher URL)
PURE Output Type: Article
Published Date: 2012-04-20
Authors: Oliver, Kathryn M.
Lenihan, Colin R.
Bruning, Ulrike
Cheong, Alex ( 0000-0003-2482-9078)
Laffey, John G.
McLoughlin, Paul
Taylor, Cormac T.
Cummins, Eoin P.

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