RESUMO
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.
Assuntos
Proteínas E1A de Adenovirus/metabolismo , Vírus de DNA Tumorais/imunologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Nucleotídeos Cíclicos/antagonistas & inibidores , Proteínas Oncogênicas Virais/metabolismo , Evasão Tumoral , Proteínas E1A de Adenovirus/química , Proteínas E1A de Adenovirus/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , DNA de Neoplasias/imunologia , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Evolução Molecular , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Redes e Vias Metabólicas , Dados de Sequência Molecular , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/genética , Proteína do Retinoblastoma/antagonistas & inibidoresRESUMO
Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.
Assuntos
Evolução Molecular , Variação Genética , Mamíferos/genética , Proteínas Nucleares/genética , Animais , Sequência de Bases , Células Cultivadas , Proteínas de Ligação a DNA , Embrião de Mamíferos/citologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Inflamassomos/metabolismo , Interferons/genética , Interferons/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Proteínas Nucleares/classificação , Proteínas Nucleares/metabolismo , Fosfoproteínas/classificação , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Filogenia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido NucleicoRESUMO
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.