NEMO lysine mutant mice reveal ROS-RelA signaling required for optimal CD40-induced humoral immunity

We created the NEMODK mouse model with germline arginine substitutions at NEMO (NF-κB essential modulator) lysines 270 and 302, key sites for post-translational modifications selectively induced by these intracellular stresses to enable NF-κB signaling in vitro.

NEMODK mice exhibited B cell-intrinsic defects in the generation of germinal center B cells and humoral responses. Mechanistically, NEMODK B cells displayed a CD40-specific NF-κB signaling defect, unrelated to acute canonical and delayed noncanonical NF-κB activity, which was accompanied by the lack of sustained NEMO monoubiquitination downstream of mitochondrial reactive oxygen species generation without relying on nuclear DNA damage.