Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans

Abstract

IKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present the first homozygous germline missense variant (c.499G > A, p.G167R) in the kinase domain of the CHUK gene, which encodes IKKα. This variant, referred to as IKKα^G167R, was found in three children from two Turkish families. IKKα^G167R is located in the activation segment of the kinase domain and affects the conserved Asp-Phe/Leu-Gly (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKα^G167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKα^G167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia, significantly reduced populations of memory T and B, MAIT, NK, Tfh, and Treg cells, and limited diversity of T and B cell receptors with evidence of autoreactivity. These patients also demonstrate heightened susceptibility to viral, bacterial, and fungal infections. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans due to skeletal and skin abnormalities, the deficiency of IKKα's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the innate and adaptive immune systems, underscoring the essential and non-redundant kinase function of IKKα in humans.