Defective nuclear IKKalpha function in patients with ectodermal dysplasia with immune deficiency.

摘要

Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-kappaB essential modulator (NEMO; also known as IkappaB kinase gamma subunit IKKgamma). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-kappaB proteins, resulting in defective expression of NF-kappaB target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-kappaB. However, cells deficient in full-length NEMO were defective in expression of NF-kappaB-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-kappaB transcription factors. TLR4-stimulated APCs from the patients were defective in IKKalpha-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-kappaB heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKKalpha restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKKalpha and offer new insights into the mechanisms underlying diminished NF-kappaB signaling in patients with EDI.