Absence of Leucine Zipper in the Natural FOXP3Δ2Δ7 Isoform Does Not Affect Dimerization but Abrogates Suppressive Capacity
Copyright policy )Absence of Leucine Zipper in the Natural FOXP3Δ2Δ7 Isoform Does Not Affect Dimerization but Abrogates Suppressive Capacity
Phenotype and function of regulatory T cells (Treg) largely depend on the presence of the transcription factor FOXP3. In contrast to mice, human Treg cells express isoforms of this protein. Besides the full length version (FOXP3fl), an isoform lacking the exon 2 (FOXP3Delta2) is co-expressed in comparable amounts. Recently, a third splice variant has been described that in addition to exon 2 also misses exon 7 (FOXP3Delta2Delta7). Exon 7 encodes for a leucine zipper motif commonly used as structural dimerization element. Mutations in exon 7 have been linked to IPEX, a severe autoimmune disease suggested to be caused by impaired dimerization of the FOXP3 protein.This study shows that the lack of exon 7 does not affect (homo-) dimerization. Moreover, the interaction of FOXP3Delta2Delta7 to RUNX1, NFAT and NF-kB appeared to be unchanged in co-immunoprecipitation experiments and reporter gene assays, when compared to FOXP3fl and FOXP3Delta2. Nevertheless, retroviral transduction with FOXP3Delta2Delta7 failed to induce the typical Treg-associated phenotype. The expression of FOXP3-induced surface molecules such as CD25 and CTLA-4 were not enhanced in FOXP3Delta2Delta7 transduced CD4+ T cells, which also failed to exhibit any suppressive capacity. Notably, however, co-expression of FOXP3fl with FOXP3Delta2Delta7 resulted in a reduction of CD25 expression by a dominant negative effect.The leucine zipper of FOXP3 does not mediate dimerization or interaction with NFAT, NF-kB and RUNX1, but is indispensable for the characteristic phenotype and function in Treg cells. FOXP3Delta2Delta7 could play a role in regulating the function of the other FOXP3 isoforms and may be involved in cancer pathogenesis, as it is overexpressed by certain malignant cells.
- Helmholtz Association of German Research Centres Germany
- Singapore Immunology Network Singapore
- National University of Singapore Singapore
- Max Delbrück Center for Molecular Medicine Germany
- National University of Singapore Libraries Singapore
interleukin 2 receptor alpha, Cancer Research, Transcription, Genetic, animal cell, protein binding, immunoprecipitation, RUNX1 protein, T-Lymphocytes, Regulatory, Mice, regulatory T lymphocyte, Bagg albino mouse, Protein Isoforms, animal, exon, gene mutation, primer DNA, gene transfer, FOXP3 protein, cancer cell, Mice, Inbred BALB C, dimerization, Retrovirus, Reverse Transcriptase Polymerase Chain Reaction, Q, article, R, NF-kappa B, Forkhead Transcription Factors, Exons, leucine zipper protein, protein function, reporter gene, immunoglobulin enhancer binding protein, Core Binding Factor Alpha 2 Subunit, isoprotein, forkhead transcription factor, Medicine, IPEX syndrome, carcinogenesis, Dimerization, Research Article, Protein Binding, Subcellular Fractions, transcription factor RUNX1, 570, phenotype, Science, transcription factor NFAT, animal experiment, transcription factor FOXP3, gene repression, protein localization, 612, Animals, Humans, controlled study, human, protein interaction, protein expression, mouse, DNA Primers, CD4+ T lymphocyte, Leucine Zippers, nonhuman, cytotoxic T lymphocyte antigen 4, Base Sequence, NFATC Transcription Factors, human cell, genetic transcription, cell function
interleukin 2 receptor alpha, Cancer Research, Transcription, Genetic, animal cell, protein binding, immunoprecipitation, RUNX1 protein, T-Lymphocytes, Regulatory, Mice, regulatory T lymphocyte, Bagg albino mouse, Protein Isoforms, animal, exon, gene mutation, primer DNA, gene transfer, FOXP3 protein, cancer cell, Mice, Inbred BALB C, dimerization, Retrovirus, Reverse Transcriptase Polymerase Chain Reaction, Q, article, R, NF-kappa B, Forkhead Transcription Factors, Exons, leucine zipper protein, protein function, reporter gene, immunoglobulin enhancer binding protein, Core Binding Factor Alpha 2 Subunit, isoprotein, forkhead transcription factor, Medicine, IPEX syndrome, carcinogenesis, Dimerization, Research Article, Protein Binding, Subcellular Fractions, transcription factor RUNX1, 570, phenotype, Science, transcription factor NFAT, animal experiment, transcription factor FOXP3, gene repression, protein localization, 612, Animals, Humans, controlled study, human, protein interaction, protein expression, mouse, DNA Primers, CD4+ T lymphocyte, Leucine Zippers, nonhuman, cytotoxic T lymphocyte antigen 4, Base Sequence, NFATC Transcription Factors, human cell, genetic transcription, cell function
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).45 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!