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1.
ACS Chem Biol ; 17(6): 1315-1320, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35580266

RESUMO

Interleukin-1 receptor-associated kinase 3 (IRAK3) is a pseudokinase mediator in the human inflammatory pathway, and ablation of its function is associated with enhanced antitumor immunity. Traditionally, pseudokinases have eluded "druggability" and have not been considered tractable targets in the pharmaceutical industry. Herein we disclose a CRISPR/Cas9-mediated knockout of IRAK3 in monocyte-derived dendritic cells that results in an increase in IL-12 production upon lipopolysaccharide (LPS) stimulation. Furthermore, we disclose and characterize Degradomer D-1, which displays selective proteasomal degradation of IRAK3 and reproduces the 1L-12p40 increases observed in the CRISPR/Cas9 knockout.


Assuntos
Citocinas , Quinases Associadas a Receptores de Interleucina-1 , Citocinas/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-12/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/metabolismo
2.
Immunity ; 19(1): 95-104, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12871642

RESUMO

Integrin ligation activates both cell adhesion and signal transduction, in part through reorganization of the actin cytoskeleton. Plastins (also known as fimbrins) are actin-crosslinking proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. Here we show that plastin-deficient polymorphonuclear neutrophils (PMN) are deficient in killing the bacterial pathogen Staphylococcus aureus in vivo and in vitro, despite normal phagocytosis. Like integrin beta2-deficient PMN, plastin-deficient PMN cannot generate an adhesion-dependent respiratory burst, because of markedly diminished integrin-dependent syk activation. Unlike beta2(-/-) PMN, plastin-deficient PMN adhere and spread normally. Deficiency of plastin thus separates the classical integrin receptor functions of adhesion and spreading from intracellular signal transduction.


Assuntos
Antígenos CD18/fisiologia , Neutrófilos/imunologia , Fosfoproteínas/fisiologia , Transdução de Sinais/fisiologia , Animais , Adesão Celular , Movimento Celular , Precursores Enzimáticos/fisiologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Neutrófilos/fisiologia , Proteínas Tirosina Quinases/fisiologia , Explosão Respiratória , Infecções Estafilocócicas/imunologia , Quinase Syk
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