# IKZF2

## Overview
IKZF2, also known as Helios, is a gene that encodes the IKAROS family zinc finger 2 protein, a member of the Ikaros family of zinc finger transcription factors. This protein is characterized by its multiple C2H2-type zinc finger domains, which are essential for its DNA-binding and protein-protein interaction capabilities (Powell2019Ikaros). As a transcription factor, IKAROS family zinc finger 2 plays a pivotal role in the regulation of immune responses, particularly within T cells, including regulatory T cells (Tregs) and effector T cells (Hetemäki2021Lossoffunction). It is involved in chromatin remodeling and transcriptional regulation through interactions with the Mi-2/NuRD complex, contributing to immune homeostasis and tolerance (Hetemäki2021Lossoffunction; Sridharan2007Predominant). Mutations in the IKZF2 gene have been linked to various immunological disorders and non-syndromic hearing loss, highlighting its clinical significance (Hetemäki2021Lossoffunction; Velde2024Exome).

## Structure
IKZF2, also known as Helios, is a member of the Ikaros family of zinc finger transcription factors. The protein structure is characterized by multiple C2H2-type zinc finger domains, which are crucial for its DNA-binding and protein-protein interaction capabilities (Powell2019Ikaros). The N-terminal zinc finger domains are responsible for DNA binding, while the C-terminal domains facilitate homo- and heterodimerization with other Ikaros family members, such as Ikaros and Aiolos (Hetemäki2021Lossoffunction; Powell2019Ikaros).

The secondary structure of IKZF2 includes alpha helices and beta sheets, stabilized by zinc ion coordination, which is typical for zinc finger proteins. The tertiary structure is further stabilized by these zinc ions, allowing for the precise folding necessary for its function (Powell2019Ikaros). IKZF2 can form both homodimers and heterodimers, indicating a quaternary structure that is essential for its role in transcriptional regulation (Hetemäki2021Lossoffunction).

Post-translational modifications, such as phosphorylation, may influence the function and localization of IKZF2, although specific modifications are not detailed in the provided context. Splice variants of IKZF2 can lead to different isoforms, which may have distinct functional properties (Lu2023A).

## Function
IKZF2, also known as Helios, is a transcription factor that plays a critical role in the regulation of immune responses in healthy human cells. It is a member of the Ikaros family of zinc finger proteins and functions primarily as a transcriptional regulator within T cells, including regulatory T cells (Tregs) and effector T cells, particularly of the CD8+ lineage (Hetemäki2021Lossoffunction). Helios is involved in chromatin remodeling through interactions with the Mi-2/NuRD complex, a major transcriptional corepressor, which is crucial for maintaining immune homeostasis (Hetemäki2021Lossoffunction; Sridharan2007Predominant).

In Tregs, Helios stabilizes the suppressive phenotype, possibly via STAT-5 mediated signaling, and prevents IL-2 production by epigenetic silencing (Hetemäki2021Lossoffunction). It is highly expressed in Tregs and is induced after TCR-mediated activation in both Tregs and effector T cells, contributing to immune tolerance and the regulation of immune responses (Hetemäki2021Lossoffunction). Helios also plays a role in the differentiation and function of mucosal-associated invariant T (MAIT) cells, which are important in fungal infections (Hetemäki2021Lossoffunction). Its activity is primarily nuclear, where it binds DNA to modulate transcription, influencing processes like immune tolerance and autoimmunity (Hetemäki2021Lossoffunction).

## Clinical Significance
Mutations in the IKZF2 gene, which encodes the Helios protein, have been associated with various immunological and non-immunological disorders. A loss-of-function mutation known as the p.Y200X variant in IKZF2 is linked to immunodeficiency characterized by dysregulated germinal center reactions and a reduction in mucosal-associated invariant T (MAIT) cells. This mutation results in increased production of proinflammatory cytokines such as IFNγ and IL-2, and an altered immune response due to the failure in upregulating HELIOS, a protein involved in T cell receptor activation (Hetemäki2021Lossoffunction).

IKZF2 variants have also been implicated in non-syndromic hearing loss. Missense variants affecting the zinc finger motifs of Helios, such as c.485A>C p.(His162Pro), c.509G>A p.(Cys170Tyr), and c.434G>T p.(Cys145Phe), co-segregate with hearing loss in several families. These variants disrupt zinc ion coordination, leading to protein destabilization and potential loss of function, contributing to hearing loss (Velde2024Exome).

Additionally, a germline heterozygous dominant negative variant of IKZF2, specifically the p.Gly136_Ser191dup Helios variant, is associated with a syndromic primary immune regulatory disorder and ICHAD, characterized by immune dysregulation and conditions such as autoimmune hemolytic anemia and atopic dermatitis (Lu2023A).

## Interactions
IKZF2, also known as Helios, is a transcription factor that participates in various protein-protein interactions crucial for its function in immune regulation. It is a member of the Ikaros family of zinc finger proteins and interacts with other family members, such as Ikaros and Aiolos, to form complexes that modulate chromatin structure and gene transcription (Hetemäki2021Lossoffunction). IKZF2 interacts with the Mi-2/NuRD chromatin remodeling complex, which is essential for its role in transcriptional regulation. A loss-of-function mutation in IKZF2 disrupts its interaction with this complex, leading to immune dysregulation (Hetemäki2021Lossoffunction).

The protein also engages in interactions with CRBN, a protein that mediates degradation, as part of targeted cancer immunotherapy strategies. The compound DKY709 has been developed to selectively degrade IKZF2 by enhancing its recruitment to CRBN, without affecting other Ikaros family members like IKZF1 and IKZF3 (Solomon2022Targeted). This interaction is significant for modulating immune responses, particularly in the context of cancer therapy (Solomon2022Targeted).

IKZF2 also binds directly to the ICOS promoter in CD4+ T helper cells, indicating its role in regulating gene expression during immune responses (Xie2021Ikzf2). These interactions highlight the multifaceted role of IKZF2 in immune cell differentiation and function.


## References


[1. (Hetemäki2021Lossoffunction) Iivo Hetemäki, Meri Kaustio, Matias Kinnunen, Nelli Heikkilä, Salla Keskitalo, Kirsten Nowlan, Simo Miettinen, Joona Sarkkinen, Virpi Glumoff, Noora Andersson, Kaisa Kettunen, Reetta Vanhanen, Katariina Nurmi, Kari K. Eklund, Johannes Dunkel, Mikko I. Mäyränpää, Heinrich Schlums, T. Petteri Arstila, Kai Kisand, Yenan T. Bryceson, Pärt Peterson, Ulla Otava, Jaana Syrjänen, Janna Saarela, Markku Varjosalo, and Eliisa Kekäläinen. Loss-of-function mutation in ikzf2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of mait cells. Science Immunology, November 2021. URL: http://dx.doi.org/10.1126/sciimmunol.abe3454, doi:10.1126/sciimmunol.abe3454. This article has 36 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/sciimmunol.abe3454)

[2. (Xie2021Ikzf2) Shihao Xie, Haixia Wei, Anping Peng, Anqi Xie, Jiajie Li, Chao Fang, Feihu Shi, Quan Yang, He Huang, Hongyan Xie, Xingfei Pan, Xu Tian, and Jun Huang. Ikzf2 regulates the development of icos+ th cells to mediate immune response in the spleen of s. japonicum-infected c57bl/6 mice. Frontiers in Immunology, August 2021. URL: http://dx.doi.org/10.3389/fimmu.2021.687919, doi:10.3389/fimmu.2021.687919. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2021.687919)

[3. (Velde2024Exome) Hedwig M. Velde, Maryam Vaseghi-Shanjani, Jeroen J. Smits, Gayatri Ramakrishnan, Jaap Oostrik, Mieke Wesdorp, Galuh Astuti, Helger G. Yntema, Lies Hoefsloot, Cris P. Lanting, Martijn A. Huynen, Anna Lehman, Stuart E. Turvey, E. Aten, M. J. van den Boogaard, F. L. J. Cals, M. F. van Dooren, F. A. Ebbens, I. Feenstra, R. H. Free, H. H. W. de Gier, T. P. M. Goderie, L. Haer-Wigman, K. Hellingman, E. H. Hoefsloot, J. R. Hof, J. van de Kamp, S. G. Kant, J. S. Klein Wassink-Ruiter, H. Kremer, M. Kriek, A. M. A. Lachmeijer, C. P. Lanting, S. M. Maas, P. Merkus, R. J. E. Pennings, A. Plomp, F. G. Ropers, L. J. C. Rotteveel, M. P. van der Schroeff, A. L. Smit, J. J. Smits, V. Vernimmen, J. C. C. Widdershoven, H. G. Yntema, Ronald J. E. Pennings, and Hannie Kremer. Exome variant prioritization in a large cohort of hearing-impaired individuals indicates ikzf2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases. Human Genetics, October 2024. URL: http://dx.doi.org/10.1007/s00439-024-02706-w, doi:10.1007/s00439-024-02706-w. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00439-024-02706-w)

[4. (Sridharan2007Predominant) Rupa Sridharan and Stephen T. Smale. Predominant interaction of both ikaros and helios with the nurd complex in immature thymocytes. Journal of Biological Chemistry, 282(41):30227–30238, October 2007. URL: http://dx.doi.org/10.1074/jbc.m702541200, doi:10.1074/jbc.m702541200. This article has 102 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m702541200)

5. (Lu2023A) A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD. This article has 0 citations.

[6. (Powell2019Ikaros) Michael D. Powell, Kaitlin A. Read, Bharath K. Sreekumar, and Kenneth J. Oestreich. Ikaros zinc finger transcription factors: regulators of cytokine signaling pathways and cd4+ t helper cell differentiation. Frontiers in Immunology, June 2019. URL: http://dx.doi.org/10.3389/fimmu.2019.01299, doi:10.3389/fimmu.2019.01299. This article has 78 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2019.01299)

7. (Solomon2022Targeted) Targeted degradation of IKZF2 for cancer immunotherapy. This article has 1 citations.