Clarifying the role of IKKα kinase in the function of the NF-κB inflammation pathway

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A signaling pathway is a series of steps, initiated by a stimulus, involving several molecules within a biological cell. These pathways are crucial for coordinating the growth, regulation and function of cells and tissues. If signaling between or within cells is deregulated, inappropriate cellular responses can lead to cancer or other diseases such as autoimmune diseases or, conversely, immune deficiencies. The NF-κB signaling pathway is involved in our immune and inflammatory responses. It can be activated in two different ways: the canonical pathway (activated rapidly by numerous stimuli) and the non-canonical pathway (activated later by more restricted stimuli). Researchers from the “Immunogenetics of Pediatric Autoimmune Diseases” laboratory at Institut Imagine looked at a patient with hypogammaglobulinemia, recurrent lung infections and Hay-Wells syndrome, who carried two mutations in the CHUK gene (one on each allele) encoding the IKKα protein.

Their results, recently published in the Journal of Experimental Medicine, showed that these two mutations in the CHUK gene altered activation of the non-canonical NF-κB pathway, but also to a lesser extent the canonical pathway, confirming a crucial role for IKKα in both pathways. These results clarify our understanding of the functioning of the NF-κB pathway, involved in numerous biological mechanisms such as intercellular communication, innate and adaptive immune response and inflammatory response. They also shed light on the role of IKKα in this signaling pathway. This gene is still little studied, as highly deleterious mutations in IKKα seem to drastically affect development. The identification of this new mutation therefore represents a breakthrough in the diagnosis of children with symptoms similar to those of the patient.

A signaling pathway is a series of steps, initiated by a stimulus, involving several molecules within a biological cell. The NF-κB pathway is a key player in immune and inflammatory responses. It can be activated by two different pathways:   

  •  The canonical pathway: which activates very rapidly and enables rapid reprogramming of immune cells in the face of an antigen or aggression.   

  • The non-canonical pathway: activates more slowly, thanks to more specific stimulation, and has a more restricted role. It is particularly important for antibody-controlled immunity.   

This NF-κB signaling pathway requires the activation of kinases, “switch” proteins that regulate numerous intracellular processes, namely IKKα (studied here) and IKKβ, both encoded by the CHUK gene. It was initially considered that IKKα had a key role in activating the non-canonical pathway, but that it was not required for the activation of the canonical pathway, itself mostly regulated by IKKβ.   

Quentin Riller, together with Frédéric Rieux-Laucat, director of the “Immunogenetics of Pediatric Autoimmune Diseases” laboratory at the Institut Imagine (Inserm, AP-HP, Université Paris Cité), have focused on a patient suffering from syndromic immunodeficiency and various immune dysregulations. In an initial study by a Dutch research team, a heterozygous mutation (present on only one of the alleles) of the CHUK gene had already been identified in this patient, without being functionally studied.   

In the patient's cells, the Institut Imagine researchers observed a significant alteration in the non-canonical NF-κB pathway. Even more surprisingly, they also observed partial defects in the canonical pathway; which was not supposed to be regulated by IKKα. The researchers then identified a second heterozygous mutation in this gene, in the other allele. The researchers thus describe for the first time composite heterozygous variants in the kinase domain of IKKα responsible for immune deficiency. 

Furthermore, reintroduction of the CHUK gene in its unmutated form restores activation of the NF-κB non-canonical pathway. This means that the correct production of IKKα can restore the proper functioning of the non-canonical pathway, raising the prospect of therapeutic leads. These results, published in Journal of Experimental Medicine, call into question the origin of the patient's disease, which would therefore no longer be linked to an IKKα mutation but to the cumulative effect of the two mutations. This underscores the need to analyze and understand the impact of each mutation, in order to establish the most accurate diagnosis possible in the case of a genetic disease. Finally, since a defect in IKKα caused the canonical pathway to vary, this study confirms that there is an interaction between the canonical and non-canonical pathways. This then changes the idea we had of the role of IKKα and broadens our understanding of NF-κB pathway deficiencies.   

This study not only broadened our knowledge of IKKα and the NF-κB pathway, but also highlighted the importance of detailed analysis of patients' genomes. In the future, these researchers would like to create a reference cohort on the IKKα gene, as already exists for other genes. Cases of IKKα mutation, such as those studied, remain very rare, however, as they are probably not very viable; nevertheless, the establishment of such a cohort would further enhance our understanding of the functioning of the NF-κB pathway, involved in many other physiological mechanisms and pathologies. 

 

 

Reference : 

Article title: Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.  

1st author et al, JExpMed, 2025  

Corresponding author : Quentin Riller and Frédéric Rieux-Laucat  

DOI : 10.1084/jem.20240843.