IPEX as a Consequence of Alternatively Spliced FOXP3

Mailer, Reiner K.

doi:10.3389/fped.2020.594375

Cited by 13 publications

(21 citation statements)

References 96 publications

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“…Moreover, alternative splicing of FOXP3 controls regulatory T cell effector functions and is associated with human atherosclerotic plaque stability [ 50 ]. Accumulated data also suggest that IPEX syndrome may be a consequence of alternatively spliced FOXP3 [ 51 ]. Finally, FOXP3 isoform profile has been linked to cardiovascular diseases [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

Wang

Yang

Cardoso

et al. 2021

IJMS

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Activating transcription factor 3 (ATF3), a transcription factor and acute stress sensor, is rapidly induced by a variety of pathophysiological signals and is essential in the complex processes in cellular stress response. FOXP3, a well-known breast and prostate tumor suppressor from the X chromosome, is a novel transcriptional repressor for several oncogenes. However, it remains unknown whether ATF3 is the target protein of FOXP3. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. Firstly, we observed that overexpression of FOXP3 reduced ATF3 protein level. Moreover, knockdown FOXP3 by siRNA increased ATF3 expression. Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in the luciferase reporter assay. Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) significantly abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, the FOXP3 binding site was found on ATF3 promoter region by deletion and mutagenesis analysis. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and that this novel event may be involved in tumor development and progression.

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Section: Discussionmentioning

confidence: 99%

Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

Wang

Yang

Cardoso

et al. 2021

IJMS

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“…It has also been demonstrated that patients with IPEX syndrome who have missense mutations and deletions in splicing sites do not have Treg CD4+CD25+Foxp3+ lymphocytes and have a more severe form of the disease. Additionally, the absence of CD4+CD25+ cells confirms the diagnosis [35]. IPEX also has high levels of IgE and IgA immunoglobulins, as well as eosinophilia, which proves that the transcription factor Foxp3 is strongly associated with the human immune response [179][180][181][182].…”

Section: Specialized Researchmentioning

confidence: 74%

“…Two of them, located between amino acids 68-76 and amino acids 239-248, are nuclear export signals which are short peptides containing hydrophobic residues targeted for export from the cell nucleus into the cytoplasm through the nuclear pore complex (Figure 2) [32]. Another example is the LXXLL motif, located between amino acids 92-96, which is involved in many proteinprotein interactions related to various aspects of transcription regulation (Figure 2) [33][34][35]. These motifs are present in many transcription factors and cofactors, mediating interactions that may activate or suppress transcription [36,37].…”

Section: Molecular Characterization Of the Foxp3 Proteinmentioning

confidence: 99%

“…The occurrence of mutations in the FOXP3 gene is associated with the development of the IPEX disease syndrome and was described for the first time in 1982 by Powell et al as a rare immunodeficiency syndrome with a genetic predisposition [176]. This disease is characterized by the presence of three specific clinical symptoms such as enteropathy with chronic diarrhea (most often acute, watery, and bloody diarrhea), endocrinopathy (insulin-dependent diabetes type I), and dermatitis (Figure 5) [35]. IPEX is a recessive disorder related to the X chromosome; therefore, it occurs only in males (in the first six months of life) and causes T lymphocyte activation, accompanied by the overproduction of cytokines, and leads to autoimmune disorders with the presence of various autoantibodies [177].…”

Section: The Role Of Foxp3 Protein In Ipex Developmentmentioning

confidence: 99%

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The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies

Mertowska

Mertowski

Podgajna

et al. 2022

JCM

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Transcription factors are an extremely important group of proteins that are responsible for the process of selective activation or deactivation of other cellular proteins, usually at the last stage of signal transmission in the cell. An important family of transcription factors that regulate the body’s response is the FOX family which plays an important role in regulating the expression of genes involved in cell growth, proliferation, and differentiation. The members of this family include the intracellular protein Foxp3, which regulates the process of differentiation of the T lymphocyte subpopulation, and more precisely, is responsible for the development of regulatory T lymphocytes. This protein influences several cellular processes both directly and indirectly. In the process of cytokine production regulation, the Foxp3 protein interacts with numerous proteins and transcription factors such as NFAT, nuclear factor kappa B, and Runx1/AML1 and is involved in the process of histone acetylation in condensed chromatin. Malfunctioning of transcription factor Foxp3 caused by the mutagenesis process affects the development of disorders of the immune response and autoimmune diseases. This applies to the impairment or inability of the immune system to fight infections due to a disruption of the mechanisms supporting immune homeostasis which in turn leads to the development of a special group of disorders called primary immunodeficiencies (PID). The aim of this review is to provide information on the role of the Foxp3 protein in the human body and its involvement in the development of two types of primary immunodeficiency diseases: IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome) and CVID (Common Variable Immunodeficiency).

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“…Two other isoforms, FOXP3Δ2Δ7 and FOXP3Δ7, have also been described in human lymphocytes and epithelial cells, but unlike FOXP3FL and FOXP3Δ2, neither appears to play a role in Treg suppressive activity ( 12 ). Therefore, the need to maintain their expression when restoring a dysregulated immune system, such as that in IPEX patients, is not clear ( 13 , 14 ). In contrast to human T cells, mice express only FOXP3FL ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Co-Expression of FOXP3FL and FOXP3Δ2 Isoforms Is Required for Optimal Treg-Like Cell Phenotypes and Suppressive Function

et al. 2021

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FOXP3 is the master transcription factor in both murine and human FOXP3+ regulatory T cells (Tregs), a T-cell subset with a central role in controlling immune responses. Loss of the functional Foxp3 protein in scurfy mice leads to acute early-onset lethal lymphoproliferation. Similarly, pathogenic FOXP3 mutations in humans lead to immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which are characterized by systemic autoimmunity that typically begins in the first year of life. However, although pathogenic FOXP3 mutations lead to overlapping phenotypic consequences in both systems, FOXP3 in human Tregs, but not mouse, is expressed as two predominant isoforms, the full length (FOXP3FL) and the alternatively spliced isoform, delta 2 (FOXP3Δ2). Here, using CRISPR/Cas9 to generate FOXP3 knockout CD4+ T cells (FOXP3KOGFP CD4+ T cells), we restore the expression of each isoform by lentiviral gene transfer to delineate their functional roles in human Tregs. When compared to FOXP3FL or FOXP3Δ2 alone, or double transduction of the same isoform, co-expression of FOXP3FL and FOXP3Δ2 induced the highest overall FOXP3 protein expression in FOXP3KOGFP CD4+ T cells. This condition, in turn, led to optimal acquisition of Treg-like cell phenotypes including downregulation of cytokines, such as IL-17, and increased suppressive function. Our data confirm that co-expression of FOXP3FL and FOXP3Δ2 leads to optimal Treg-like cell function and supports the need to maintain the expression of both when engineering therapeutics designed to restore FOXP3 function in otherwise deficient cells.

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IPEX as a Consequence of Alternatively Spliced FOXP3

Cited by 13 publications

References 96 publications

Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

Forkhead Box Protein P3 (FOXP3) Represses ATF3 Transcriptional Activity

The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies

Co-Expression of FOXP3FL and FOXP3Δ2 Isoforms Is Required for Optimal Treg-Like Cell Phenotypes and Suppressive Function

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