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

Maroof Hasan, James Koch, Dinesh Rakheja, Asit K. Pattnaik, James Brugarolas, Igor Dozmorov, Beth Levine, Edward K. Wakeland, Min Ae Lee-Kirsch, Nan Yan

Research output: Contribution to journalArticle

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)61-71
Number of pages11
JournalNature Immunology
Volume14
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hasan, M., Koch, J., Rakheja, D., Pattnaik, A. K., Brugarolas, J., Dozmorov, I., Levine, B., Wakeland, E. K., Lee-Kirsch, M. A., & Yan, N. (2013). Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. Nature Immunology, 14(1), 61-71. https://doi.org/10.1038/ni.2475