RESUMO
Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.
Assuntos
Células Dendríticas/imunologia , Infecções por Herpesviridae/imunologia , Imunidade Inata/imunologia , Muromegalovirus/metabolismo , Nucleotídeos Cíclicos/metabolismo , Sistemas do Segundo Mensageiro , Vaccinia virus/metabolismo , Vacínia/imunologia , Vírion/metabolismo , Animais , Chlorocebus aethiops , Citosol/imunologia , Citosol/metabolismo , Citosol/virologia , Células Dendríticas/virologia , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/metabolismo , Células HeLa , Humanos , Imunidade Inata/genética , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/genética , Vaccinia virus/genética , Células Vero , Vírion/genética , Montagem de VírusRESUMO
Natural killer (NK) cells are involved in immune responses against tumors and microbes. NK-cell activation is regulated by intrinsic and extrinsic mechanisms that ensure NK tolerance and efficacy. Here, we show that the cytoplasmic signaling molecules Dok1 and Dok2 are tyrosine phosphorylated upon NK-cell activation. Overexpression of Dok proteins in human NK cells reduces cell activation induced by NK-cell-activating receptors. Dok1 and Dok2 gene ablation in mice induces an NK-cell maturation defect and leads to increased IFN-γ production induced by activating receptors. Taken together, these results reveal that Dok1 and Dok2 proteins are involved in an intrinsic negative feedback loop downstream of NK-cell-activating receptors in mouse and human.