Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation
Abstract
NF-κB is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-κB mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-κB is regulated through interactions with IκB inhibitory proteins, which are in turn regulated by the inhibitor of κB kinase (IKK) complex. Together, these 3 components form the core of the NF-κB signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-κB pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-κB is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-κB pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and the...Continue Reading
References
Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses
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