NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 06 2023
22 06 2023
Historique:
received:
08
09
2022
accepted:
06
06
2023
medline:
26
6
2023
pubmed:
23
6
2023
entrez:
22
6
2023
Statut:
epublish
Résumé
Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
Identifiants
pubmed: 37349339
doi: 10.1038/s41467-023-39295-7
pii: 10.1038/s41467-023-39295-7
pmc: PMC10287742
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Blood Proteins
0
CTLA-4 Antigen
0
LRBA protein, human
EC 2.7.10.-
NBEAL2 protein, human
0
CTLA4 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3728Informations de copyright
© 2023. The Author(s).
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