Hypercapnia Induces Cleavage and Nuclear Localization of RelB Protein, Giving Insight into CO2 Sensing and Signaling

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

doi:10.1074/jbc.m112.347971

Cited by 49 publications

(44 citation statements)

References 34 publications

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“…Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2)(3)(4).…”

mentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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mentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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“…In the same experimental series, hypercapnia was also shown to inhibit p65 translocation in mouse embryonic fibroblast cells in response to lipopolysaccharide injury. In a further study by the same group [36], RelB -a protein of the noncanonical NFkB pathway -was shown to undergo cleavage and subsequent translocation to the nucleus under conditions of increased carbon dioxide; these effects were independent of pH changes induced by buffering cell culture media.…”

Section: Molecular Mechanismsmentioning

confidence: 92%

“…The cellular mechanisms of action of carbon dioxide in cerebral microvascular endothelial cells and human fetal astrocytes have shed light on Carbon dioxide has been shown to confer positive anti-inflammatory effects by increasing the translocation of RelB and impairing the translocation of p65 [35,36]. Carbon dioxide has also been demonstrated to increase the endocytosis of the Na,K-ATPase transporter [34,37,38 && ] leading to reduced edema clearance from injured lungs.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Hypercapnia

Masterson

Otulakowski²,

Kavanagh

2015

Current Opinion in Critical Care

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“…9,10 Oliver et al further showed that elevated CO 2 causes reversible nuclear translocation of the noncanonical NF-κB component RelB, a negative regulator of innate immune gene expression. 11 In addition, we have shown that hypercapnia inhibits phagocytosis, autophagy, and bacterial killing in mouse and human macrophages. 9,12 Interestingly, elevated CO 2 has immunosuppressive effects in Drosophila , as well as in mammalian systems.…”

Section: Introductionmentioning

confidence: 94%

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

et al. 2016

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Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically.

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Hypercapnia Induces Cleavage and Nuclear Localization of RelB Protein, Giving Insight into CO2 Sensing and Signaling

Cited by 49 publications

References 34 publications

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Hypercapnia

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

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