ABSTRACT
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.
Subject(s)
Adenovirus E1A Proteins/metabolism , DNA Tumor Viruses/immunology , DNA-Binding Proteins/metabolism , Membrane Proteins/antagonists & inhibitors , Nucleotides, Cyclic/antagonists & inhibitors , Oncogene Proteins, Viral/metabolism , Tumor Escape , Adenovirus E1A Proteins/chemistry , Adenovirus E1A Proteins/genetics , Amino Acid Motifs , Amino Acid Sequence , DNA, Neoplasm/immunology , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Evolution, Molecular , HEK293 Cells , HeLa Cells , Host-Pathogen Interactions , Humans , Metabolic Networks and Pathways , Molecular Sequence Data , Oncogene Proteins, Viral/chemistry , Oncogene Proteins, Viral/genetics , Retinoblastoma Protein/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Evolution, Molecular , Genetic Variation , Mammals/genetics , Nuclear Proteins/genetics , Animals , Base Sequence , Cells, Cultured , DNA-Binding Proteins , Embryo, Mammalian/cytology , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression , HEK293 Cells , HeLa Cells , Humans , Inflammasomes/metabolism , Interferons/genetics , Interferons/metabolism , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Nuclear Proteins/classification , Nuclear Proteins/metabolism , Phosphoproteins/classification , Phosphoproteins/genetics , Phosphoproteins/metabolism , Phylogeny , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Nucleic AcidABSTRACT
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.
