Journal ArticleDOI
Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation
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TLDR
Human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF‐κB pathway are reviewed and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.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 they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-κB pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.read more
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Journal ArticleDOI
NF-κB signaling in inflammation
TL;DR: This review will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-σB inhibition.
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An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death
Amer A. Beg,David Baltimore +1 more
TL;DR: Reintroduction of RelA into RelA−/− fibroblasts resulted in enhanced survival, demonstrating that the presence ofrelA is required for protection from TNF-α.
Journal ArticleDOI
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Ranjan Sen,David Baltimore +1 more
TL;DR: In this paper, an electrophoretic mobility shift assay with end-labeled DNA fragments was used to characterize proteins that bind to the immunoglobulin (Ig) heavy chain and the kappa light chain enhancers.
Journal ArticleDOI
The NF-κB Family of Transcription Factors and Its Regulation
Andrea Oeckinghaus,Sankar Ghosh +1 more
TL;DR: The NF-kappaB pathway is a paradigm for understanding general principles of signal transduction and gene regulation as well as other pathway-specific mediators, and the transcription factors are themselves extensively modified.