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Hasan, M, Koch, J, Rakheja, D, Pattnaik, AK, Brugarolas, J, Dozmorov, I, Levine, B, Wakeland, EK, Lee-Kirsch, MA and Yan, N (2013) Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. Nat. Immunol. 14:61-71


The sensing of viral nucleic acids by the innate immune system triggers the production of type I interferons, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through interferon-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulated the activation of a subset of ISGs independently of interferon. Both Trex1(-/-) mouse cells and Trex1-mutant human cells had high expression of genes encoding antiviral molecules ('antiviral genes') and were refractory to viral infection. The interferon-independent activation of antiviral genes in Trex1(-/-) cells required the adaptor STING, the kinase TBK1 and the transcription factors IRF3 and IRF7. We also found that Trex1-deficient cells had an expanded lysosomal compartment, altered subcellular localization of the transcription factor TFEB and diminished activity of the regulator mTORC1. Together our data identify Trex1 as a regulator of lysosomal biogenesis and interferon-independent activation of antiviral genes and show that dysregulation of lysosomes can elicit innate immune responses.


PubMed PMC3522772 Online version:10.1038/ni.2475


Animals; Antigens, Viral/immunology; Exodeoxyribonucleases/genetics; Exodeoxyribonucleases/metabolism; HeLa Cells; Humans; Immunity, Active/genetics; Interferons/immunology; Lysosomes/physiology; Mice; Mice, Knockout; Mutation/genetics; Organelle Biogenesis; Phosphoproteins/genetics; Phosphoproteins/metabolism; RNA Virus Infections/immunology; RNA Viruses/immunology; RNA, Small Interfering/genetics