Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.

<h4>Background</h4>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 (FOXP3...

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Autores principales:	Reiner K W Mailer, Kirsten Falk, Olaf Rötzschke
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fc223c0039604569b610f0f258034b8b
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spelling	oai:doaj.org-article:fc223c0039604569b610f0f258034b8b2021-11-25T06:21:49ZAbsence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.1932-620310.1371/journal.pone.0006104https://doaj.org/article/fc223c0039604569b610f0f258034b8b2009-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19568423/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Principal findings</h4>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.<h4>Conclusions</h4>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.Reiner K W MailerKirsten FalkOlaf RötzschkePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 7, p e6104 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reiner K W Mailer Kirsten Falk Olaf Rötzschke Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
description	<h4>Background</h4>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.<h4>Principal findings</h4>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.<h4>Conclusions</h4>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.
format	article
author	Reiner K W Mailer Kirsten Falk Olaf Rötzschke
author_facet	Reiner K W Mailer Kirsten Falk Olaf Rötzschke
author_sort	Reiner K W Mailer
title	Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
title_short	Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
title_full	Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
title_fullStr	Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
title_full_unstemmed	Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.
title_sort	absence of leucine zipper in the natural foxp3delta2delta7 isoform does not affect dimerization but abrogates suppressive capacity.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/fc223c0039604569b610f0f258034b8b
work_keys_str_mv	AT reinerkwmailer absenceofleucinezipperinthenaturalfoxp3delta2delta7isoformdoesnotaffectdimerizationbutabrogatessuppressivecapacity AT kirstenfalk absenceofleucinezipperinthenaturalfoxp3delta2delta7isoformdoesnotaffectdimerizationbutabrogatessuppressivecapacity AT olafrotzschke absenceofleucinezipperinthenaturalfoxp3delta2delta7isoformdoesnotaffectdimerizationbutabrogatessuppressivecapacity
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Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity.

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