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

Authors

Maroof Hasan, University of Texas Southwestern Medical Center
James Koch, University of Texas Southwestern Medical Center
Dinesh Rakheja, University of Texas Southwestern Medical Center
Asit K. Pattnaik, University of Nebraska-LincolnFollow
James Brugarolas, University of Texas Southwestern Medical Center
Igor Dozmorov, University of Texas Southwestern Medical Center
Beth Levine, University of Texas Southwestern Medical center
Edward K. Wakeland, University of Texas Southwestern Medical center
Min Ae Lee-kirsch, Children’s Hospital, Technical University Dresden
Nan Yan, University of Texas Southwestern Medical center

Document Type

Article

Date of this Version

2013

Citation

Nat Immunol. 2013 January ; 14(1): 61–71. doi:10.1038/ni.2475.

Comments

Copy right 2013 Nature Publishing group

Abstract

Innate immune sensing of viral nucleic acids triggers type I interferon (IFN) production, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through IFN-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulates the activation of a subset of ISGs independently of IFN. Both Trex1−/− mouse and TREX1-mutant human cells express high levels of antiviral genes and are refractory to viral infections. The IFN-independent activation of antiviral genes in Trex1−/− cells requires STING, TBK1 and IRF3 and IRF7. We also found that Trex1-deficient cells display expanded lysosomal compartment, altered subcellular localization of the transcription factor EB (TFEB), and reduced mTORC1 activity. Together, our data identify Trex1 as a regulator of lysosomal biogenesis and IFN-independent activation of antiviral genes, and shows dysregulation of lysosomes can elicit innate immune responses.