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

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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 1 2013

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Interferons
Transcriptional Activation
Antiviral Agents
Genes
Transcription Factors
Interferon Type I
Virus Diseases
Lysosomes
Innate Immunity
Nucleic Acids
Immune System
Phosphotransferases
Gene Expression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. / Hasan, Maroof; Koch, James; Rakheja, Dinesh; Pattnaik, Asit K; Brugarolas, James; Dozmorov, Igor; Levine, Beth; Wakeland, Edward K.; Lee-Kirsch, Min Ae; Yan, Nan.

In: Nature Immunology, Vol. 14, No. 1, 01.01.2013, p. 61-71.

Research output: Contribution to journalArticle

Hasan, M, Koch, J, Rakheja, D, Pattnaik, AK, Brugarolas, J, Dozmorov, I, Levine, B, Wakeland, EK, Lee-Kirsch, MA & Yan, N 2013, 'Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes', Nature Immunology, vol. 14, no. 1, pp. 61-71. https://doi.org/10.1038/ni.2475
Hasan, Maroof ; Koch, James ; Rakheja, Dinesh ; Pattnaik, Asit K ; Brugarolas, James ; Dozmorov, Igor ; Levine, Beth ; Wakeland, Edward K. ; Lee-Kirsch, Min Ae ; Yan, Nan. / Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. In: Nature Immunology. 2013 ; Vol. 14, No. 1. pp. 61-71.
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