# NFKBIA

## Overview
The NFKBIA gene encodes the IκBα protein, a pivotal inhibitor within the NF-κB signaling pathway, which plays a crucial role in regulating immune and inflammatory responses. IκBα is categorized as an inhibitory protein that functions by binding to the NF-κB transcription factor complex, specifically the p50-p65 heterodimer, and sequestering it in the cytoplasm. This sequestration prevents NF-κB from translocating to the nucleus and activating genes involved in inflammation and immune responses (Karin2000Phosphorylation; Ali2010Functional). The regulation of NF-κB activity by IκBα is modulated through phosphorylation and ubiquitination, which signal IκBα for degradation, thereby allowing NF-κB to enter the nucleus (DiDonato1997A). The NFKBIA gene itself is subject to feedback regulation by NF-κB, ensuring a tightly controlled balance of immune signaling (Arenzana-Seisdedos1995Inducible). Mutations in NFKBIA are linked to various clinical conditions, including immunodeficiencies and certain cancers, highlighting its significance in maintaining immune homeostasis (Boisson2017Human; Lake2009Mutations).

## Structure
The NFKBIA gene encodes the IκBα protein, which functions as an inhibitor of the NF-κB transcription factor. The primary structure of IκBα is characterized by the presence of ankyrin repeat domains. These domains are essential for the protein's ability to bind NF-κB, thereby inhibiting its activity. The secondary structure of IκBα includes alpha helices within these ankyrin repeats, contributing to the protein's stability and function.

In terms of tertiary structure, the ankyrin repeats fold to form a stable inhibitory complex that effectively sequesters NF-κB in the cytoplasm, preventing its translocation to the nucleus where it would activate target genes. This folding is crucial for the protein's inhibitory function.

Post-translational modifications play a significant role in regulating the function and degradation of IκBα. Phosphorylation and ubiquitination are key modifications that signal the protein for degradation, thus modulating the NF-κB signaling pathway. These modifications ensure that the inhibition of NF-κB is tightly controlled and can be rapidly reversed in response to cellular signals. 

The structural features of IκBα, including its ankyrin repeat domains and post-translational modifications, are critical for its role in regulating NF-κB activity.

## Function
The NFKBIA gene encodes the IκBα protein, a crucial regulator of the NF-κB signaling pathway in human cells. IκBα functions by binding to the NF-κB transcription factor, specifically the p50-p65 heterodimer, and sequestering it in the cytoplasm. This interaction prevents NF-κB from translocating to the nucleus, thereby inhibiting the transcription of proinflammatory genes (Karin2000Phosphorylation; Ali2010Functional). 

Upon cellular stimulation by factors such as tumor necrosis factor (TNF) or interleukin 1 (IL-1), IκBα is phosphorylated by the IκB kinase (IKK) complex, leading to its ubiquitination and subsequent degradation by the proteasome. This degradation releases NF-κB, allowing it to enter the nucleus and activate the transcription of genes involved in immune and inflammatory responses (Ali2010Functional; DiDonato1997A). 

The NFKBIA gene itself is a target of NF-κB, creating a feedback loop where newly synthesized IκBα can re-enter the nucleus, bind NF-κB, and facilitate its export back to the cytoplasm, thus terminating the signal (Karin2000Phosphorylation; Arenzana-Seisdedos1995Inducible). This regulatory mechanism is essential for maintaining immune homeostasis and preventing excessive inflammation (Ali2010Functional).

## Clinical Significance
Mutations in the NFKBIA gene, which encodes the IκBα protein, are associated with several clinical conditions, primarily involving immune system dysfunction. One significant condition is anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an autosomal dominant disorder characterized by impaired NF-κB-mediated responses due to gain-of-function mutations in NFKBIA. These mutations enhance the inhibitory activity of IκBα, preventing its phosphorylation and degradation, leading to severe immunodeficiency with symptoms such as B-cell deficiency and recurrent infections (Boisson2017Human; Yoshioka2013Autosomal).

Specific mutations, such as p.Ser32Cys and p.Ser36Tyr, have been identified in patients with EDA-ID, affecting phosphorylation sites crucial for IκBα degradation and NF-κB activation. These mutations result in varied clinical phenotypes, including ectodermal dysplasia, systemic inflammation, and immunodeficiency (Chear2022A; Yoshioka2013Autosomal). The p.Ser36Tyr mutation, for instance, is associated with milder ectodermal dysplasia and fewer infections (Yoshioka2013Autosomal).

NFKBIA mutations are also implicated in classical Hodgkin lymphoma (cHL), where they contribute to the pathogenesis by affecting NF-κB signaling pathways, although they are not a unifying feature in non-EBV-associated cases (Lake2009Mutations).

## Interactions
NFKBIA, also known as IκBα, is a critical inhibitor of the NF-κB transcription factor complex. It physically interacts with NF-κB subunits, such as p65/RelA, c-Rel, and p50, sequestering them in the cytoplasm and preventing their nuclear translocation and subsequent activation of gene transcription (Curran2002Polymorphic). This interaction is crucial for regulating immune and inflammatory responses, as well as cell proliferation and apoptosis (Song2020Silencing).

NFKBIA is involved in a regulatory loop where its transcription is activated by NF-κB, creating a feedback mechanism that controls NF-κB activity (Paciolla2011Nuclear). The protein's interaction with NF-κB is modulated by phosphorylation, which marks NFKBIA for degradation, thereby releasing NF-κB to enter the nucleus (Curran2002Polymorphic).

In addition to its role in the NF-κB pathway, NFKBIA interacts with β-catenin, a key player in cell signaling and cancer progression. This interaction inhibits β-catenin-mediated signaling, affecting processes such as cell proliferation, migration, and invasion in cervical cancer cells (Chen2021Study). These interactions highlight NFKBIA's multifaceted role in cellular signaling pathways.


## References


[1. (Chear2022A) Chai Teng Chear, Bader Abdul Kader El Farran, Marina Sham, Kavetha Ramalingam, Lokman Mohd Noh, Intan Hakimah Ismail, Mei Yee Chiow, Mohd Farid Baharin, Adiratna Mat Ripen, and Saharuddin Bin Mohamad. A novel de novo nfkbia missense mutation associated to ectodermal dysplasia with dysgammaglobulinemia. Genes, 13(10):1900, October 2022. URL: http://dx.doi.org/10.3390/genes13101900, doi:10.3390/genes13101900. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/genes13101900)

[2. (Paciolla2011Nuclear) M. Paciolla, R. Boni, F. Fusco, A. Pescatore, L. Poeta, M. V. Ursini, M. B. Lioi, and M. G. Miano. Nuclear factor-kappa-b-inhibitor alpha (nfkbia) is a developmental marker of nf- b/p65 activation during in vitro oocyte maturation and early embryogenesis. Human Reproduction, 26(5):1191–1201, February 2011. URL: http://dx.doi.org/10.1093/humrep/der040, doi:10.1093/humrep/der040. This article has 39 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/humrep/der040)

[3. (Song2020Silencing) Kai‐You Song, Xian‐Zhao Zhang, Feng Li, and Qing‐Rong Ji. Silencing of atp2b1‐as1 contributes to protection against myocardial infarction in mouse via blocking nfkbia‐mediated nf‐κb signalling pathway. Journal of Cellular and Molecular Medicine, 24(8):4466–4479, March 2020. URL: http://dx.doi.org/10.1111/jcmm.15105, doi:10.1111/jcmm.15105. This article has 24 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jcmm.15105)

[4. (Yoshioka2013Autosomal) Takakazu Yoshioka, Ryuta Nishikomori, Junichi Hara, Keiko Okada, Yoshiko Hashii, Ikuo Okafuji, Seishiro Nodomi, Tomoki Kawai, Kazushi Izawa, Hidenori Ohnishi, Takahiro Yasumi, Tatsutoshi Nakahata, and Toshio Heike. Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel nfkbia mutation, p.ser36tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation. Journal of Clinical Immunology, 33(7):1165–1174, July 2013. URL: http://dx.doi.org/10.1007/s10875-013-9924-z, doi:10.1007/s10875-013-9924-z. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s10875-013-9924-z)

[5. (Ali2010Functional) Salman Ali, Aaron Hirschfeld, Rachel Victor, Edgardo S Fortuno, Tobias R Kollmann, and Stuart E Turvey. Functional characterization of human variants of nfkbia: a key regulator of immune responsiveness implicated in susceptibility to infectious and inflammatory disease. Allergy, Asthma & Clinical Immunology, November 2010. URL: http://dx.doi.org/10.1186/1710-1492-6-s3-p2, doi:10.1186/1710-1492-6-s3-p2. This article has 1 citations.](https://doi.org/10.1186/1710-1492-6-s3-p2)

[6. (Lake2009Mutations) Annette Lake, Lesley A. Shield, Pablo Cordano, Daniel T.Y. Chui, Julie Osborne, Shauna Crae, Katherine S. Wilson, Sabrina Tosi, Samantha J.L. Knight, Stefan Gesk, Reiner Siebert, Ron T. Hay, and Ruth F. Jarrett. Mutations of nfkbia, encoding iκbα, are a recurrent finding in classical hodgkin lymphoma but are not a unifying feature of non‐ebv‐associated cases. International Journal of Cancer, 125(6):1334–1342, July 2009. URL: http://dx.doi.org/10.1002/ijc.24502, doi:10.1002/ijc.24502. This article has 74 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/ijc.24502)

[7. (Chen2021Study) Mengyue Chen, Xiaolong Liang, Zhiqing Liang, and Limei Zhao. Study on the effect and mechanism of <scp>nfkbia</scp> on cervical cancer progress in vitro and in vivo. Journal of Obstetrics and Gynaecology Research, 47(11):3931–3942, August 2021. URL: http://dx.doi.org/10.1111/jog.14947, doi:10.1111/jog.14947. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jog.14947)

[8. (Karin2000Phosphorylation) Michael Karin and Yinon Ben-Neriah. Phosphorylation meets ubiquitination: the control of nf-κb activity. Annual Review of Immunology, 18(1):621–663, April 2000. URL: http://dx.doi.org/10.1146/annurev.immunol.18.1.621, doi:10.1146/annurev.immunol.18.1.621. This article has 3698 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1146/annurev.immunol.18.1.621)

[9. (Boisson2017Human) Bertrand Boisson, Anne Puel, Capucine Picard, and Jean-Laurent Casanova. Human iκbα gain of function: a severe and syndromic immunodeficiency. Journal of Clinical Immunology, 37(5):397–412, June 2017. URL: http://dx.doi.org/10.1007/s10875-017-0400-z, doi:10.1007/s10875-017-0400-z. This article has 57 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s10875-017-0400-z)

[10. (Curran2002Polymorphic) Joanne E. Curran, Stephen R. Weinstein, and Lyn R. Griffiths. Polymorphic variants of nfkb1 and its inhibitory protein nfkbia, and their involvement in sporadic breast cancer. Cancer Letters, 188(1–2):103–107, December 2002. URL: http://dx.doi.org/10.1016/s0304-3835(02)00460-3, doi:10.1016/s0304-3835(02)00460-3. This article has 53 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/s0304-3835(02)00460-3)

[11. (Arenzana-Seisdedos1995Inducible) Fernando Arenzana-Seisdedos, Jill Thompson, M. S. Rodriguez, Françoise Bachelerie, D. Thomas, and Ronald T. Hay. Inducible nuclear expression of newly synthesized iκbα negatively regulates dna-binding and transcriptional activities of nf-κb. Molecular and Cellular Biology, 15(5):2689–2696, May 1995. URL: http://dx.doi.org/10.1128/mcb.15.5.2689, doi:10.1128/mcb.15.5.2689. This article has 348 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.15.5.2689)

[12. (DiDonato1997A) Joseph A. DiDonato, Makio Hayakawa, David M. Rothwarf, Ebrahim Zandi, and Michael Karin. A cytokine-responsive iκb kinase that activates the transcription factor nf-κb. Nature, 388(6642):548–554, August 1997. URL: http://dx.doi.org/10.1038/41493, doi:10.1038/41493. This article has 1781 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/41493)