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

Kathryn M. Oliver, Colin R. Lenihan, Ulrike Bruning, Alex Cheong, John G. Laffey, Paul McLoughlin, Cormac T. Taylor, Eoin P. Cummins

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)14004-14011
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number17
DOIs
Publication statusPublished - 20 Apr 2012

Fingerprint

Hypercapnia
Carbon Monoxide
Proteins
Acidosis
Glycogen Synthase Kinase 3
Hypoventilation
Lung
Pulmonary diseases
Adult Respiratory Distress Syndrome
Lung Injury
Fibroblasts
Processing
Carbon Dioxide
Chronic Obstructive Pulmonary Disease
Lung Diseases
Ventilation
Molecular Weight
Epithelial Cells
Molecular weight
Molecules

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

Cite this

Oliver, Kathryn M. ; Lenihan, Colin R. ; Bruning, Ulrike ; Cheong, Alex ; Laffey, John G. ; McLoughlin, Paul ; Taylor, Cormac T. ; Cummins, Eoin P. / Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 17. pp. 14004-14011.
@article{bc317db5da9d4f38afa17c521729fe7d,
title = "Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling",
abstract = "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 3{\ss} 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.",
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",
author = "Oliver, {Kathryn M.} and Lenihan, {Colin R.} and Ulrike Bruning and Alex Cheong and Laffey, {John G.} and Paul McLoughlin and Taylor, {Cormac T.} and Cummins, {Eoin P.}",
year = "2012",
month = "4",
day = "20",
doi = "10.1074/jbc.M112.347971",
language = "English",
volume = "287",
pages = "14004--14011",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "17",

}

Oliver, KM, Lenihan, CR, Bruning, U, Cheong, A, Laffey, JG, McLoughlin, P, Taylor, CT & Cummins, EP 2012, 'Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling', Journal of Biological Chemistry, vol. 287, no. 17, pp. 14004-14011. https://doi.org/10.1074/jbc.M112.347971

Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling. / Oliver, Kathryn M.; Lenihan, Colin R.; Bruning, Ulrike; Cheong, Alex; Laffey, John G.; McLoughlin, Paul; Taylor, Cormac T.; Cummins, Eoin P.

In: Journal of Biological Chemistry, Vol. 287, No. 17, 20.04.2012, p. 14004-14011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling

AU - Oliver, Kathryn M.

AU - Lenihan, Colin R.

AU - Bruning, Ulrike

AU - Cheong, Alex

AU - Laffey, John G.

AU - McLoughlin, Paul

AU - Taylor, Cormac T.

AU - Cummins, Eoin P.

PY - 2012/4/20

Y1 - 2012/4/20

N2 - 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.

AB - 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.

KW - animals

KW - carbon dioxide

KW - tumor cell line

KW - cell nucleus

KW - epithelial cells

KW - fibroblasts

KW - gene expression regulation

KW - humans

KW - hypercapnia

KW - mice

KW - biological models

KW - RNA interference

KW - signal transduction

KW - transcription factor

KW - RelB

UR - http://www.jbc.org/content/287/17/14004

U2 - 10.1074/jbc.M112.347971

DO - 10.1074/jbc.M112.347971

M3 - Article

C2 - 22396550

VL - 287

SP - 14004

EP - 14011

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 17

ER -