Carbon Dioxide-Dependent Regulation of NF-κB Family Members RelB and P100 Gives Molecular Insight Into CO2-dependent Immune Regulation

Ciara E Keogh, Carsten C Scholz, Javier Rodriguez, Andrew C Selfridge, Alex Von Kriegsheim, Eoin P Cummins

Research output: Contribution to journalArticlepeer-review

Abstract

CO2 is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO2 > ≈ 50mmHg) is a feature of several lung pathologies e.g. chronic obstructive pulmonary disease (COPD). Hypercapnia is associated with increased susceptibility to bacterial infections and suppression of inflammatory signaling. The NF-κB pathway has been implicated in these effects, however, the molecular mechanisms underpinning cellular sensitivity of the NF-κB pathway to CO2 is not fully elucidated. Here we identify several novel CO2-dependent changes in the NF-κB pathway. NF-κB family members p100 and RelB translocate to the nucleus in response to CO2. A cohort of RelB protein-protein interactions (e.g. with Raf-1 and IκBα) are altered by CO2 exposure, while others are maintained (e.g. with p100). RelB is processed by CO2 in a manner dependent on a key C-terminal domain located in its transactivation domain. Loss of the RelB transactivation domain alters NF-κB -dependent transcriptional activity and loss of p100 alters sensitivity of RelB to CO2. Thus, we provide molecular insight into the CO2-sensitivity of the NF-κB pathway and implicate altered RelB/p100-dependent signaling in the CO2-dependent regulation of inflammatory signaling.
Original languageEnglish
Pages (from-to)jbc.M116.755090
JournalJournal of Biological Chemistry
Early online date15 May 2017
DOIs
Publication statusE-pub ahead of print - 15 May 2017

Keywords

  • carbon dioxide
  • chronic obstructive pulmonary disease (COPD)
  • Inflammation
  • innate immunity
  • NF-kB transcription factor
  • CO2
  • Hypercapnia
  • RelB
  • Immunity
  • p100

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