Trex1 Regulates Lysosomal Biogenesis and Interferon-Independent Activation of Antiviral Genes

Nat Immunol. 2013 Jan;14(1):61-71. doi: 10.1038/ni.2475. Epub 2012 Nov 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Antigens, Viral
  • Phosphoproteins
  • RNA, Small Interfering
  • Interferons
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1