RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling.
Proc Natl Acad Sci U S A
; 118(28)2021 07 13.
Article
em En
| MEDLINE
| ID: mdl-34260403
ABSTRACT
Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic Yersinia species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1ß release, which is critical for anti-Yersinia defense. During in vivo infection, IL-1ß neutralization increases bacterial burden in wild-type but not Gsdme-deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling.
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Base de dados:
MEDLINE
Assunto principal:
Yersinia pseudotuberculosis
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Transdução de Sinais
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Proteína Serina-Treonina Quinases de Interação com Receptores
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Imunidade Inata
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Macrófagos
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Proteínas de Neoplasias
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Neutrófilos
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article