IKKß primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network.
Immunity
; 55(12): 2271-2284.e7, 2022 12 13.
Article
em En
| MEDLINE
| ID: mdl-36384135
ABSTRACT
The NLRP3 inflammasome plays a central role in antimicrobial defense as well as in the context of sterile inflammatory conditions. NLRP3 activity is governed by two independent signals the first signal primes NLRP3, rendering it responsive to the second signal, which then triggers inflammasome formation. Our understanding of how NLRP3 priming contributes to inflammasome activation remains limited. Here, we show that IKKß, a kinase activated during priming, induces recruitment of NLRP3 to phosphatidylinositol-4-phosphate (PI4P), a phospholipid enriched on the trans-Golgi network. NEK7, a mitotic spindle kinase that had previously been thought to be indispensable for NLRP3 activation, was redundant for inflammasome formation when IKKß recruited NLRP3 to PI4P. Studying iPSC-derived human macrophages revealed that the IKKß-mediated NEK7-independent pathway constitutes the predominant NLRP3 priming mechanism in human myeloid cells. Our results suggest that PI4P binding represents a primed state into which NLRP3 is brought by IKKß activity.
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Base de dados:
MEDLINE
Assunto principal:
Inflamassomos
/
Proteína 3 que Contém Domínio de Pirina da Família NLR
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article