RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation.
NLR Family, Pyrin Domain-Containing 3 Protein
/ genetics
Inflammasomes
/ metabolism
Humans
RAC2 GTP-Binding Protein
Gain of Function Mutation
Macrophages
/ immunology
rac GTP-Binding Proteins
/ genetics
Interleukin-1beta
/ metabolism
Animals
p21-Activated Kinases
/ genetics
Mice
Interleukin-18
/ genetics
Signal Transduction
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:
07 Oct 2024
07 Oct 2024
Historique:
received:
31
08
2023
revised:
15
02
2024
accepted:
17
07
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
30
8
2024
Statut:
ppublish
Résumé
A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.
Identifiants
pubmed: 39212656
pii: 276948
doi: 10.1084/jem.20231562
pii:
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
Inflammasomes
0
RAC2 GTP-Binding Protein
EC 3.6.1.-
rac GTP-Binding Proteins
EC 3.6.5.2
Interleukin-1beta
0
p21-Activated Kinases
EC 2.7.11.1
Interleukin-18
0
PAK1 protein, human
EC 2.7.11.1
NLRP3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondation pour la Recherche Médicale
ID : EQU202403018053
Organisme : Agence Nationale de la Recherche
ID : ANR-17-CE15-0001
Organisme : E-Rare Joint Transnational Call for Proposals 2015
ID : EuroCID
Organisme : Association pour la Recherche sur le Cancer
ID : RAC15014AAA
Organisme : Université Côte d'Azur
Organisme : France Génomique National Infrastructure
Organisme : Canceropôle PACA
Informations de copyright
© 2024 Doye et al.