@article{da6ebe7d31b843ea9f62592ee1e7d073,
title = "Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes",
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.",
author = "Maroof Hasan and James Koch and Dinesh Rakheja and Pattnaik, {Asit K.} and Brugarolas, {James B} and Igor Dozmorov and Beth Levine and Wakeland, {Edward K} and Lee-Kirsch, {Min Ae} and Nan Yan",
note = "Funding Information: 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{\textquoteright}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.).",
year = "2013",
month = jan,
doi = "10.1038/ni.2475",
language = "English (US)",
volume = "14",
pages = "61--71",
journal = "Nature immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "1",
}