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.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Maroof
authors.initials: M
authors.lastname: Hasan
authors.forename: James
authors.initials: J
authors.lastname: Koch
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Asit K
authors.initials: AK
authors.lastname: Pattnaik
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Min Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007110:Immunity, Active / Q000235:genetics; D007372:Interferons / Q000276:immunology; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D001678:Organelle Biogenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012327:RNA Virus Infections / Q000276:immunology*; D012328:RNA Viruses / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000956:Antigens, Viral; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D007372:Interferons; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1