Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0006104
Title: Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity
Authors: Mailer R.K.W.
Falk K.
Rötzschke O.
Keywords: cytotoxic T lymphocyte antigen 4
immunoglobulin enhancer binding protein
interleukin 2 receptor alpha
isoprotein
leucine zipper protein
transcription factor FOXP3
transcription factor NFAT
transcription factor RUNX1
forkhead transcription factor
FOXP3 protein, human
immunoglobulin enhancer binding protein
isoprotein
leucine zipper protein
primer DNA
RUNX1 protein, human
transcription factor NFAT
transcription factor RUNX1
animal cell
animal experiment
article
cancer cell
carcinogenesis
CD4+ T lymphocyte
cell function
controlled study
dimerization
exon
gene mutation
gene repression
gene transfer
genetic transcription
human
human cell
immunoprecipitation
IPEX syndrome
mouse
nonhuman
phenotype
protein binding
protein expression
protein function
protein interaction
protein localization
regulatory T lymphocyte
reporter gene
Retrovirus
animal
Bagg albino mouse
cell fractionation
chemistry
genetics
immunology
metabolism
nucleotide sequence
physiology
reverse transcription polymerase chain reaction
Mus
Animals
Base Sequence
Core Binding Factor Alpha 2 Subunit
Dimerization
DNA Primers
Exons
Forkhead Transcription Factors
Humans
Leucine Zippers
Mice
Mice, Inbred BALB C
NF-kappa B
NFATC Transcription Factors
Protein Binding
Protein Isoforms
Reverse Transcriptase Polymerase Chain Reaction
Subcellular Fractions
T-Lymphocytes, Regulatory
Transcription, Genetic
Issue Date: 2009
Publisher: Public Library of Science
Citation: Mailer R.K.W., Falk K., Rötzschke O. (2009). Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity. PLoS ONE 4 (7) : e6104. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0006104
Abstract: Background: 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. Principal Findings: 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 CTLA4 were not enhanced in FOXP3D2D7 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. Conclusions: 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. © 2009 Mailer et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/165604
ISSN: 19326203
DOI: 10.1371/journal.pone.0006104
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