Comment on Temmerman et al, page 2324
Even though the mutations in NEMO were linked to immunodeficiency 5 years ago, unraveling the exact role of NEMO in host defense took a while to figure out. Now we have more answers to “how?”
Nuclear factor-κB (NF-κB) is critical in modulating the expression of immunoregulatory genes in host defense, inflammation, and apoptosis. It plays a central role in regulating the transcription of cytokines, adhesion molecules, and other mediators. NF-κB essential modulator (NEMO) is an integral part of the IκB kinase (IKK) complex and regulates NF-κB activity by alterations in the phosphorylation, ubiquitination, and degradation of its inhibitor (IκB).1-3
The molecular mechanisms that lead to NF-κB activation and the role played by NEMO in regulation of NF-κB have recently been the focus of many researchers. Discovery of adapter proteins and signaling complexes that lead to NEMO ubiquitination has been critical for our understanding of stimuli-driven activation of NF-κB.4 Unraveling this process helps to clairfy the clinical and cellular outcomes of mutations in NEMO. Hypomorphic mutations in NEMO impair NF-κB function and lead to ectodermal dysplasia with immunodeficiency (ED-ID), characterized by increased susceptibility to pyogenic bacteria, viruses, and nonpathogenic mycobacterial infections.1-3 Patients with one specific mutation have been reported with osteopetrosis and lymphedema.2 At a cellular level, these patients failed to respond to stimulation with CD40 ligand (CD40L), Toll-like receptor (TLR) ligands, interleukin-1 (IL-1), and tumor necrosis factor α (TNFα). In this issue of Blood, Temmerman and colleagues report impaired CD40L stimulation in monocyte-derived dendritic cells (DCs) from patients with a specific mutation (C417R) in the zinc finger domain of NEMO. This study complements their previous report on the impaired B-cell class-switch recombination in ED-ID patients with impaired zinc finger domain.5 With this study, they show an absent NEMO ubiquitination along with absent c-Rel activity upon CD40L stimulation, defective IL-12 production, impaired DC maturation, but intact lipopolysaccharide (LPS)–induced NF-κB activity and NEMO ubiquitination. They conclude that ubiquitination of NEMO in DCs is differential and stimuli specific, especially when the zinc finger domain is impaired. The benefit of cytokine treatment inpatients with ED-ID has been an issue that may help to be resolved by this study. Temmerman and colleagues show that interferon-γ (IFN-γ) could enhance NF-κB signaling acting as an in vitro costimulator for CD40L, partially enhancing NF-κB signaling via RelA activation (but without any effect on c-Rel activity) and rescuing DC maturation in vitro.
In this paper, by using gene expression profiling, Temmerman and colleagues identify genomic targets that are dependent on the presence of activated c-Rel. These studies identify genes that are normally highly up-regulated by CD40L and IFN-γ in control DCs (eg, IL-12p35), but are not up-regulated in ED-ID DCs. They demonstrate very well the importance of CD40L-induced NEMO ubiquitination, NF-κB signaling, and IL-12 production in host defense against susceptibility to environmental pathogens, especially to mycobacteria. Temmerman and colleagues conclude that the vast differences in the phenotypes of patients with ED-ID may be the result of altered stimuli-specific ubiquitination caused by specific NEMO mutations. ▪
