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

Maroof Hasan et al. Nat Immunol. 2013. 14(1):61-71.

Speaker: Mei-Ling Lai (賴玫伶)                                   Time: 15:10~16:00, Mar 20, 2013

Commentator: Dr. Yao Chang (張堯博士)                   Place: Room 601

Abstract

        Detection of nucleic acids and induction of type I interferons (IFNs) are fundamental steps in antiviral defense. IFNs activates interferon-stimulated genes (ISGs) to limit virus replication and spread. ISGs also can be activated in an interferon-independent manner; however, the precise mechanisms remain unknown. Trex1, an exonuclease that resides on the endoplasmic reticulum, is a negative regulator of the sensing of cytosolic human immunodeficiency virus (HIV) DNA by the innate immune system. The authors wondered whether Trex1 inhibits interferon responses to other viruses beyond HIV and/or if the mere loss of Trex1 function in a cell would elicit innate immune responses and establish an antiviral state. The authors found that Trex1^-/- did not regulate the type I IFNs response to vesicular stomatitis virus, influenza virus, Sendai virus and West Nile virus but impaired viruses replicaion. They found Trex1^-/- activate IFNs-independent induction of ISGs in mice that still requires the adaptor STING, the kinase TBK1,the transcription factors IRF3¹ and IRF7. Furthermore, the authors also found that late endosome and lysosome seemed to be more abundant in Trex1^−/− cells. Moreover, the loss of Trex1 activates lysosomal biogenesis through inhibition of mTORC1 and altered subcellular localization of the transcription factor TFEB. The new finding of this study is that lysosomal biogenesis led to IFNs-independent induction of ISGs that Trex1 regulates lysosomal biogenesis through TFEB and mTORC1.

Reference

1.         Noyce RS, Collins SE, Mossman KL. Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped virions. Journal of virology 2006, 80(1): 226-235.