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IKK-related genetic diseases: probing NF-κB functions in humans and other matters

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An Erratum to this article was published on 24 February 2015

Abstract

The transcription factor NF-κB plays a key role in numerous physiological processes such as inflammation, immunity, cell proliferation or control of cell death. Its activation is tightly controlled by a kinase complex, IκB kinase (IKK), composed of three core proteins: IKK1/IKKα, IKK2/IKKβ and NEMO/IKKγ. The first two are structurally related kinases whereas the third one is a regulatory subunit exhibiting affinity for upstream activators modified by polyubiquitin chains. Over the years, several inherited diseases caused by mutations of each of the three subunits of IKK have been identified in humans together with diseases caused by mutations of several of its substrates. They are associated with very specific and complex phenotypes involving a broad range of abnormalities such as impaired innate and acquired immune response, perturbed skin development and defects of the central nervous system. Here, we summarize the diverse clinical, cellular and molecular manifestations of IKK-related genetic diseases and show that studying patient-related mutations affecting the IKK subunits and some of their substrates offers the opportunity to understand the various functions of NF-κB in humans, complementing studies performed with mouse models. This analysis also provides glimpses about putative functions of IKK subunits that may be NF-κB-independent.

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Acknowledgments

A.S is supported by a CEA/IRTELIS grant. We thank C. Gautheron for expert artwork and Incontinentia Pigmenti France for support.

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Authors and Affiliations

  1. INSERM U1038, iRTSV, CEA Grenoble, Grenoble, France

    Anna Senegas, Alice Gentil Dit Maurin & Gilles Courtois

  2. Université Grenoble Alpes, Grenoble, France

    Anna Senegas, Alice Gentil Dit Maurin & Gilles Courtois

  3. Department of Gastroenterology, University Hospital RWTH Aachen, Aachen, Germany

    Jérémie Gautheron

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  1. Anna Senegas
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  2. Jérémie Gautheron
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  3. Alice Gentil Dit Maurin
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  4. Gilles Courtois
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Corresponding author

Correspondence to Gilles Courtois.

Additional information

A. Senegas and J. Gautheron contributed equally to this study.

Patients exhibiting NIK mutations have been identified by Willmann et al. (Nat Commun 5:5360, 2014. doi:10.1038/ncomms6360). They suffer from an immunodeficiency presenting similarities with the one observed in NFKBK2 mutated patients but with more severe signs.

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Senegas, A., Gautheron, J., Maurin, A.G.D. et al. IKK-related genetic diseases: probing NF-κB functions in humans and other matters. Cell. Mol. Life Sci. 72, 1275–1287 (2015). https://doi.org/10.1007/s00018-014-1793-y

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