RESUMO
The detection of intracellular nucleic acids is a fundamental mechanism of host defense against infections. The dysregulated nucleic acid sensing, however, is a major cause for a number of autoimmune diseases. In this study, we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for both intracellular DNA- and RNA-induced immune responses. We found that in both human and mouse cells, the deletion of G3BP1 led to the dampened cGAS activation by DNA and the insufficient binding of RNA by RIG-I. We further found that resveratrol (RSVL), a natural compound found in grape skin, suppressed both intracellular DNA- and RNA-induced type I IFN production through inhibiting G3BP1. Importantly, using experimental mouse models for Aicardi-Goutières syndrome, an autoimmune disorder found in humans, we demonstrated that RSVL effectively alleviated intracellular nucleic acid-stimulated autoimmune responses. Thus, our study demonstrated a broader role of G3BP1 in sensing different kinds of intracellular nucleic acids and presented RSVL as a potential treatment for autoimmune conditions caused by dysregulated nucleic acid sensing.
Assuntos
Autoimunidade/genética , DNA Helicases/deficiência , DNA Helicases/metabolismo , Espaço Intracelular/metabolismo , Ácidos Nucleicos/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/deficiência , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/deficiência , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/deficiência , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Transdução de Sinais/genética , Células A549 , Animais , Autoimunidade/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA Helicases/antagonistas & inibidores , DNA Helicases/genética , Fibroblastos/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Espaço Intracelular/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/antagonistas & inibidores , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/genética , Resveratrol/administração & dosagem , Transdução de Sinais/imunologia , TransfecçãoRESUMO
Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.
Assuntos
Inflamassomos/genética , Macrófagos/imunologia , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Choque Séptico/genética , Sequência de Aminoácidos , Animais , Enzimas Desubiquitinantes/genética , Enzimas Desubiquitinantes/imunologia , Escherichia coli/química , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteína Quinase 8 Ativada por Mitógeno/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fosforilação , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Choque Séptico/induzido quimicamente , Choque Séptico/mortalidade , Choque Séptico/patologia , Transdução de Sinais , Análise de SobrevidaRESUMO
CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.