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.