Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation

Abstract

CO₂ is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO₂ >≈50 mm Hg) is a feature of several lung pathologies, e.g. chronic obstructive pulmonary disease. 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 are 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, although 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.

Keywords: CO2; NF-κB transcription factor; RelB; carbon dioxide; chronic obstructive pulmonary disease (COPD); hypercapnia; immunity; inflammation; innate immunity; p100.