Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome

Détails

ID Serval
serval:BIB_49073892EB29
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Synthèse (review): revue aussi complète que possible des connaissances sur un sujet, rédigée à partir de l'analyse exhaustive des travaux publiés.
Collection
Publications
Titre
Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome
Périodique
Sci Transl Med
Auteur⸱e⸱s
Taylor M. D., Sadhukhan S., Kottangada P., Ramgopal A., Sarkar K., D'Silva S., Selvakumar A., Candotti F., Vyas Y. M.
ISSN
1946-6242 (Electronic)
ISSN-L
1946-6234
Statut éditorial
Publié
Date de publication
2010
Volume
2
Numéro
37
Pages
37ra44
Langue
anglais
Notes
Taylor, Matthew D
Sadhukhan, Sanjoy
Kottangada, Ponnappa
Ramgopal, Archana
Sarkar, Koustav
D'Silva, Sheryl
Selvakumar, Annamalai
Candotti, Fabio
Vyas, Yatin M
eng
AI0797621/AI/NIAID NIH HHS/
R01 AI073561/AI/NIAID NIH HHS/
Z99 HG999999/Intramural NIH HHS/
Z01 HG000122-11/Intramural NIH HHS/
G1001690/Medical Research Council/United Kingdom
AI073561/AI/NIAID NIH HHS/
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Sci Transl Med. 2010 Jun 23;2(37):37ra44. doi: 10.1126/scitranslmed.3000813.
Résumé
The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (TH1) immunity alongside intact TH2 immunity. This suggests a role for WASp in patterning T(H) subtype immunity, yet the molecular basis for the TH1-TH2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level. In primary TH1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a TH2 regulator gene) or RORc (a TH17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates TH1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating TH1 cells. During TH1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference-mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under TH1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired TH1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the TBX21 promoter to dysregulated adaptive immunity.
Mots-clé
Actins/metabolism, Cell Differentiation, Cell Nucleus/*metabolism, Cells, Cultured, Cellular Reprogramming/genetics, Chromatin/metabolism, DNA/metabolism, Epigenesis, Genetic, Genetic Loci/genetics, Genome, Human/genetics, Histones/metabolism, Humans, Immunity/*immunology, Methylation, Mutant Proteins/metabolism, Promoter Regions, Genetic/genetics, Protein Binding, Protein Transport, T-Box Domain Proteins/genetics/metabolism, Th1 Cells/cytology/*immunology, Transcription, Genetic, Wiskott-Aldrich Syndrome/*immunology/metabolism/pathology/*physiopathology, Wiskott-Aldrich Syndrome Protein/deficiency/*metabolism
Pubmed
Création de la notice
01/11/2017 10:29
Dernière modification de la notice
20/08/2019 13:56
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