Abstract:
:We have found that FOXP3 is an oligomeric component of a large supramolecular complex. Certain FOXP3 mutants with single amino acid deletions in the leucine zipper domain of FOXP3 are associated with the X-linked autoimmunity-allergic dysregulation (XLAAD) and immunodysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome in humans. We report that the single amino acid deletion found in human XLAAD/IPEX patients within the leucine zipper domain of FOXP3 does not disrupt its ability to join the larger protein complex, but eliminates FOXP3 homo-oligomerization as well as heteromerization with FOXP1. We found that the zinc finger-leucine zipper domain region of FOXP3 is sufficient to mediate both homodimerization and homotetramerization. However, the same domain region from XLAAD/IPEX FOXP3 containing an E251 deletion prevents oligomerizaton and the protein remains monomeric. We also found that wild-type FOXP3 directly binds to the human IL-2 promoter, but the E251 deletion in FOXP3 in XLAAD/IPEX patient's T cells disrupts its association with the IL-2 promoter in vivo and in vitro, and limits repression of IL-2 transcription after T-cell activation. Our results suggest that compromising FOXP3 homo-oligomerization and hetero-oligomerization with the FOXP1 protein impairs DNA-binding properties leading to distinct biochemical phenotypes in humans with the XLAAD/IPEX autoimmune syndrome. This study explains some features of the pathogenesis of a disease syndrome that arises as a consequence of specific assembly failure of a transcriptional repressor due to certain mutations within the FOXP3 leucine zipper.
journal_name
Int Immunoljournal_title
International immunologyauthors
Li B,Samanta A,Song X,Iacono KT,Brennan P,Chatila TA,Roncador G,Banham AH,Riley JL,Wang Q,Shen Y,Saouaf SJ,Greene MIdoi
10.1093/intimm/dxm043subject
Has Abstractpub_date
2007-07-01 00:00:00pages
825-35issue
7eissn
0953-8178issn
1460-2377pii
dxm043journal_volume
19pub_type
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journal_title:International immunology
pub_type: 杂志文章
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journal_title:International immunology
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更新日期:2009-08-01 00:00:00
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journal_title:International immunology
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/4.11.1303
更新日期:1992-11-01 00:00:00
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journal_title:International immunology
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journal_title:International immunology
pub_type: 杂志文章,评审
doi:10.1093/intimm/dxx059
更新日期:2017-12-30 00:00:00
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pub_type: 杂志文章
doi:10.1093/intimm/5.6.591
更新日期:1993-06-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxt046
更新日期:2014-02-01 00:00:00
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journal_title:International immunology
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更新日期:2000-05-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxh012
更新日期:2004-01-01 00:00:00
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doi:10.1093/intimm/5.9.1011
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pub_type: 杂志文章
doi:10.1093/intimm/7.9.1519
更新日期:1995-09-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxh213
更新日期:2005-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/intimm/11.9.1395
更新日期:1999-09-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/13.1.13
更新日期:2001-01-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxh024
更新日期:2004-01-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxh195
更新日期:2005-02-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxg108
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journal_title:International immunology
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更新日期:2004-08-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/intimm/9.1.81
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更新日期:1991-07-01 00:00:00
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journal_title:International immunology
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doi:10.1093/intimm/dxn128
更新日期:2009-01-01 00:00:00
abstract::Naturally occurring CD4(+)CD25(+) regulatory T cells (nT(R)) comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. Here we demonstrate that the level of phosphorylation of the TCR zeta-chain is approximately 1.5- to 4-fold higher in nT(R) as compared with CD4(+)CD25...
journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxm021
更新日期:2007-04-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/13.4.507
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxn081
更新日期:2008-10-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/dxg038
更新日期:2003-03-01 00:00:00
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journal_title:International immunology
pub_type: 杂志文章,评审
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更新日期:2018-09-25 00:00:00
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journal_title:International immunology
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doi:10.1093/intimm/dxz010
更新日期:2019-04-26 00:00:00
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journal_title:International immunology
pub_type: 杂志文章
doi:10.1093/intimm/6.8.1177
更新日期:1994-08-01 00:00:00
abstract::Antigen engagement of the TCR may lead to activation of mature T cells while inducing deletion or positive selection of immature thymocytes. Using thymocytes from TCR transgenic mice recognizing the allo-antigen H-2Kb we investigated whether double-positive CD4+CD8+ (DP) thymocytes constitute a particular developmenta...
journal_title:International immunology
pub_type: 杂志文章
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