Frédéric Rieux-Laucat

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

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.