BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation.
J Cell Biol
; 223(2)2024 02 05.
Article
em En
| MEDLINE
| ID: mdl-38078859
ABSTRACT
TLR/IL-1R signaling plays a critical role in sensing various harmful foreign pathogens and mounting efficient innate and adaptive immune responses, and it is tightly controlled by intracellular regulators at multiple levels. In particular, TOLLIP forms a constitutive complex with IRAK1 and sequesters it in the cytosol to maintain the kinase in an inactive conformation under unstimulated conditions. However, the underlying mechanisms by which IRAK1 dissociates from TOLLIP to activate TLR/IL-1R signaling remain obscure. Herein, we show that BLK positively regulates TLR/IL-1R-mediated inflammatory response. BLK-deficient mice produce less inflammatory cytokines and are more resistant to death upon IL-1ß challenge. Mechanistically, BLK is preassociated with IL1R1 and IL1RAcP in resting cells. IL-1ß stimulation induces heterodimerization of IL1R1 and IL1RAcP, which further triggers BLK autophosphorylation at Y309. Activated BLK directly phosphorylates TOLLIP at Y76/86/152 and further promotes TOLLIP dissociation from IRAK1, thereby facilitating TLR/IL-1R-mediated signal transduction. Overall, these findings highlight the importance of BLK as an active regulatory component in TLR/IL-1R signaling.
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Base de dados:
MEDLINE
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Transdução de Sinais
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Citocinas
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Quinases da Família src
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Quinases Associadas a Receptores de Interleucina-1
Limite:
Animals
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China