A neomorphic mutation in the interferon activation domain of IRF4 causes a dominant primary immunodeficiency.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
05 06 2023
05 06 2023
Historique:
received:
28
07
2022
revised:
10
01
2023
accepted:
10
02
2023
entrez:
14
3
2023
pubmed:
15
3
2023
medline:
17
3
2023
Statut:
ppublish
Résumé
Here, we report on a heterozygous interferon regulatory factor 4 (IRF4) missense variant identified in three patients from a multigeneration family with hypogammaglobulinemia. Patients' low blood plasmablast/plasma cell and naïve CD4 and CD8 T cell counts contrasted with high terminal effector CD4 and CD8 T cell counts. Expression of the mutant IRF4 protein in control lymphoblastoid B cell lines reduced the expression of BLIMP-1 and XBP1 (key transcription factors in plasma cell differentiation). In B cell lines, the mutant IRF4 protein as wildtype was found to bind to known IRF4 binding motifs. The mutant IRF4 failed to efficiently regulate the transcriptional activity of interferon-stimulated response elements (ISREs). Rapid immunoprecipitation mass spectrometry of endogenous proteins indicated that the mutant and wildtype IRF4 proteins differed with regard to their respective sets of binding partners. Our findings highlight a novel mechanism for autosomal-dominant primary immunodeficiency through altered protein binding by mutant IRF4 at ISRE, leading to defective plasma cell differentiation.
Identifiants
pubmed: 36917008
pii: 213935
doi: 10.1084/jem.20221292
pmc: PMC10037104
pii:
doi:
Substances chimiques
Interferon Regulatory Factors
0
interferon regulatory factor-4
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 Thouenon et al.
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