Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes

M Hasan, J Koch, D Rakheja, AK Pattnaik… - Nature …, 2013 - nature.com
M Hasan, J Koch, D Rakheja, AK Pattnaik, J Brugarolas, I Dozmorov, B Levine
Nature immunology, 2013nature.com
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 …
Abstract
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.
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