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

Nature Immunology volume 14, pages 61–71 (2013)Cite this article

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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.

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Figure 1: Impaired VSV replication in Trex1-deficient cells.
Figure 2: Trex1-deficient cells have broad antiviral resistance.
Figure 3: Interferon-independent activation of a subset of ISGs in Trex1-deficient cells.
Figure 4: Selective activation of ISGs in TREX1 mutant fibroblasts.
Figure 5: Interferon-independent activation of ISGs in Trex1 deficient cells requires STING, TBK1, IRF3 and IRF7.
Figure 6: Trex1 negatively regulates lysosomal biogenesis.
Figure 7: Trex1 regulates lysosomal biogenesis via TFEB and mTORC1.

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Acknowledgements

We thank D. Stetson (University of Washington) for wild-type, Trex1−/− and Trex1−/−Irf3−/− primary MEFs and Trex1+/− mice, under agreement with D. Barnes and T. Lindahl (Cancer Research UK); R. Orchard and N. Alto for assistance with live cell confocal microscopy; R. Sumpter for assistance with fluorescence microscopy; Z.J. Chen (UT Southwestern Medical Center) for Sendai virus, Ifnar1−/− MEFs and discussions; M. Gale (University of Washington) for West Nile virus; B. Fontoura (UT Southwestern Medical Center) for influenza virus; Z. Zou for technical assistance; M. Whitt (University of Tennessee Health Science Center) for antibody to VSV; the Electron Microscopy Laboratory at Children's Medical Center for electron microscopy; J. Lieberman for critical reading of the manuscript; and members of the Yan laboratory for discussions. Supported by UT Southwestern Medical Center (N.Y.), the US National Institutes of Health (AI093795 and AI098569 to N.Y.; CA129387 to J.B.; and AI057156 to B.L.), The Alliance for Lupus Research (N.Y.) and Deutsche Forschungsgemeinschaft (LE 1074/4-1 to M.A.L.-K.).

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Authors and Affiliations

  1. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Maroof Hasan, James Koch, James Brugarolas, Beth Levine & Nan Yan

  2. Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA

    Maroof Hasan, James Koch, Beth Levine & Nan Yan

  3. Department of Pathology, Children's Medical Center, UT Southwestern Medical Center, Dallas, Texas, USA

    Dinesh Rakheja

  4. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska, USA

    Asit K Pattnaik

  5. Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska, USA

    Asit K Pattnaik

  6. Department of Developmental Biology, UT Southwestern Medical Center, Dallas, Texas, USA

    James Brugarolas

  7. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA

    James Brugarolas

  8. Department of Immunology, UT Southwestern Medical Center, Dallas, Texas, USA

    Igor Dozmorov & Edward K Wakeland

  9. Center for Autophagy Research, UT Southwestern Medical Center, Dallas, Texas, USA

    Beth Levine

  10. Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas, USA

    Beth Levine

  11. Children's Hospital, Technical University Dresden, Dresden, Germany

    Min Ae Lee-Kirsch

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Contributions

M.H. and N.Y. designed and did most of the experiments; J.K. helped with the experiments; M.A.L.-K. provided human cells and advice; D.R. did electron microscopy; A.K.P., J.B. and B.L. contributed reagents and advice; E.K.W. and I.D. helped analyze the data; and M.H. and N.Y. wrote the paper.

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Correspondence to Nan Yan.

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Hasan, M., Koch, J., Rakheja, D. et al. Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. Nat Immunol 14, 61–71 (2013). https://doi.org/10.1038/ni.2475

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