# NFKBID

## Overview
NFKBID is a gene that encodes the protein IκBNS, a nonconventional member of the IκB family involved in the regulation of the NF-κB signaling pathway. Unlike classical IκB proteins, which primarily function in the cytoplasm, IκBNS is localized in the nucleus and acts as both an activator and inhibitor of NF-κB-dependent gene expression, depending on the cellular context and stimuli (Arnold2012A). As a nuclear protein, IκBNS plays a pivotal role in modulating immune responses, particularly in the regulation of cytokine transcription and the development of specific B cell subsets. It is essential for the differentiation of extrafollicular antibody-secreting cells and supports both T-independent and T-dependent humoral immunity (Souza2020Nfkbidis). The gene's involvement in immune regulation and its interactions with NF-κB subunits underscore its significance in maintaining immune homeostasis and its potential implications in autoimmune diseases (Schuster2012IκBNS).

## Function
The NFKBID gene encodes the IκBNS protein, which is a nonconventional modulator of the NF-κB signaling pathway. Unlike classical IκB proteins that are primarily cytoplasmic, IκBNS is located in the nucleus and can function as both an activator and inhibitor of NF-κB-dependent gene expression, depending on the cell type and stimuli (Arnold2012A). IκBNS plays a crucial role in regulating immune responses by modulating the transcription of various cytokines. In T cells, it positively regulates IL-2 transcription, while in macrophages, it negatively regulates IL-6 and IL-12p40 expression in response to lipopolysaccharide (LPS) stimulation (Arnold2012A).

IκBNS is essential for the development and function of specific B cell subsets, including marginal zone (MZ) and B1 B cells, and is critical for the differentiation of extrafollicular antibody-secreting cells (ASCs) that mediate T-independent antibody responses (Arnold2012A). It also supports early plasma blast differentiation and IgG1 responses to T-dependent antigens, highlighting its role in both T-independent and T-dependent humoral immunity (Souza2020Nfkbidis). The protein's activity in these processes underscores its importance in maintaining effective immune responses and cellular homeostasis.

## Clinical Significance
Mutations and alterations in the expression of the NFKBID gene, also known as IκBNS, have been implicated in various autoimmune conditions and immune system dysregulation. In the context of Type 1 Diabetes (T1D), a hypermorphic allele of NFKBID has been associated with impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in NOD mice, a model for studying T1D. This impaired deletion contributes to the autoimmune destruction of insulin-producing pancreatic beta cells, a hallmark of T1D. While reducing NFKBID expression can enhance the negative selection of these autoreactive T cells, it paradoxically accelerates T1D onset due to a decrease in regulatory lymphocyte populations, such as Tregs and Bregs, which are crucial for maintaining immune tolerance (Presa2018A).

NFKBID also plays a significant role in humoral immunity. Mutations in this gene, such as those found in 'bumble' mice, lead to impaired antibody responses, particularly affecting B-1 and B-2 cell compartments. These mutations result in defects in T-independent IgM and T-dependent IgG responses, highlighting the gene's essential role in antibody production and immune regulation (Souza2020Nfkbidis; Arnold2012A).

## Interactions
NFKBID, also known as IκBNS, is involved in various interactions with NF-κB family members, influencing their activity in immune responses. It interacts with the NF-κB subunits p50 and c-Rel, but not with p65, to modulate transcriptional activity. These interactions are crucial for the regulation of the Foxp3 gene, which is essential for the development of regulatory T cells (Tregs) (Schuster2012IκBNS). IκBNS does not contain a DNA-binding motif itself, so it requires interaction with NF-κB subunits to associate with DNA, particularly binding to the Foxp3 promoter and CNS3, a region involved in chromatin opening during Foxp3 induction (Schuster2012IκBNS).

In the context of Type 1 Diabetes in NOD mice, NFKBID acts as an enhancer of NF-κB activity during the negative selection of autoreactive CD8+ T cells, interacting with c-Rel to contribute to Foxp3 expression in Tregs (Presa2018A). These interactions highlight the dual role of NFKBID as both an inhibitor and enhancer of NF-κB activities, depending on the cellular context and protein partners involved (Presa2018A).


## References


1. (Souza2020Nfkbidis) Nfkbidis required for immunity and antibody responses toToxoplasma gondii. This article has 2 citations.

[2. (Schuster2012IκBNS) Marc Schuster, Rainer Glauben, Carlos Plaza-Sirvent, Lisa Schreiber, Michaela Annemann, Stefan Floess, Anja A. Kühl, Linda K. Clayton, Tim Sparwasser, Klaus Schulze-Osthoff, Klaus Pfeffer, Jochen Huehn, Britta Siegmund, and Ingo Schmitz. Iκbns protein mediates regulatory t cell development via induction of the foxp3 transcription factor. Immunity, 37(6):998–1008, December 2012. URL: http://dx.doi.org/10.1016/j.immuni.2012.08.023, doi:10.1016/j.immuni.2012.08.023. This article has 72 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.immuni.2012.08.023)

[3. (Arnold2012A) Carrie N. Arnold, Elaine Pirie, Pia Dosenovic, Gerald M. McInerney, Yu Xia, Nathaniel Wang, Xiaohong Li, Owen M. Siggs, Gunilla B. Karlsson Hedestam, and Bruce Beutler. A forward genetic screen reveals roles for nfkbid , zeb1 , and ruvbl2 in humoral immunity. Proceedings of the National Academy of Sciences, 109(31):12286–12293, July 2012. URL: http://dx.doi.org/10.1073/pnas.1209134109, doi:10.1073/pnas.1209134109. This article has 84 citations.](https://doi.org/10.1073/pnas.1209134109)

[4. (Presa2018A) Maximiliano Presa, Jeremy J. Racine, Jennifer R. Dwyer, Deanna J. Lamont, Jeremy J. Ratiu, Vishal Kumar Sarsani, Yi-Guang Chen, Aron Geurts, Ingo Schmitz, Timothy Stearns, Jennifer Allocco, Harold D. Chapman, and David V. Serreze. A hypermorphic nfkbid allele contributes to impaired thymic deletion of autoreactive diabetogenic cd8+ t cells in nod mice. The Journal of Immunology, 201(7):1907–1917, October 2018. URL: http://dx.doi.org/10.4049/jimmunol.1800465, doi:10.4049/jimmunol.1800465. This article has 15 citations.](https://doi.org/10.4049/jimmunol.1800465)