PMID:24598055

Citation	Xu, J, Zoltick, PW, Gamero, AM and Gallucci, S' (2014) TLR ligands up-regulate Trex1 expression in murine conventional dendritic cells through type I Interferon and NF-κB-dependent signaling pathways. J. Leukoc. Biol. '
Abstract	Mutations in the Trex1 are associated with a spectrum of type I IFN-dependent autoimmune diseases. Trex1 plays an essential role in preventing accumulation of excessive cytoplasmic DNA, avoiding cell-intrinsic innate DNA sensor activation and suppressing activation of type I IFN-stimulated and -independent antiviral genes. Trex1 also helps HIV to escape cytoplasmic detection by DNA sensors. However, regulation of Trex1 in innate immune cells remains elusive. We report that murine cDCs have high constitutive expression of Trex1 in vitro and in vivo in the spleen. In resting bone marrow-derived cDCs, type I IFNs up-regulate Trex1 expression via the IFNAR-mediated signaling pathway (STAT1- and STAT2-dependent). DC activation induced by TLR3, -4, -7, and -9 ligands also augments Trex1 expression through autocrine IFN-β production and triggering of the IFN signaling pathway, whereas TLR4 ligand LPS also stimulates an early expression of Trex1 through IFN-independent NF-κB-dependent signaling pathway. Furthermore, retroviral infection also induces Trex1 up-regulation in cDCs, as we found that a gene therapy HIV-1-based lentiviral vector induces significant Trex1 expression, suggesting that Trex1 may affect local and systemic administration of gene-therapy vehicles. Our data indicate that Trex1 is induced in cDCs during activation upon IFN and TLR stimulation through the canonical IFN signaling pathway and suggest that Trex1 may play a role in DC activation during infection and autoimmunity. Finally, these results suggest that HIV-like viruses may up-regulate Trex1 to increase their ability to escape immunosurveillance.
Links	PubMed Online version:10.1189/jlb.2A0713-393RR
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:STAT1		GO:0060337: type I interferon signaling pathway	ECO:0000315:		P		This protein forms a heterodimer with STAT2 which then functions to increase expression of Trex1 (three prime repair exonuclease 1) STAT knockout resulted in no increase in transcription while also knockout of Stat2 did not increase transcription. WT with both did show increased transcription of Trex1. Figure 2D and C along with figure 4 D graph and E.	complete CACAO 9649
MOUSE:STAT1	involved_in	GO:0060337: type I interferon signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:STAT2		GO:0060337: type I interferon signaling pathway	ECO:0000315:		P		Upon INF alpha stimulation this protein STAT2 forms a heterodimer with STAT1 where upon it increases transcription of Three prime repair exonuclease 1 Trex1 this is demonstrated by knock out of Stat2 which did not have an increase in Trex1 expression with stimulation of IFN alpha. Similar events happened with knockout of STAT1, these were shown in figures 2 c and D along with Figure 4 C,D, and E.	complete CACAO 9650
MOUSE:STAT2	involved_in	GO:0060337: type I interferon signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:INAR1		GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000315:		P		Interferon alpha receptor 1 knockouts show no increase in three prime repair exonuclease 1 (Trex1) expression of mRNA to interferon alpha whereas comparison with WT stimulation there is an increased expression of Trex1 mRNA as shown in figure 2 A graph 1 and figure 4 B at 6 hours.	complete CACAO 9652
MOUSE:INAR1		GO:0032728: positive regulation of interferon-beta production	ECO:0000315:		P		Knockout of Interferon alpha receptor 1 had did not increase production of Interferon beta mRNA with stimulation of interferon Alpha whereas the WT showed an increase in production of IFN beta with IFN alpha stimulation these were demonstrated in figure 2A graph 2.	complete CACAO 9653
MOUSE:INAR1	involved_in	GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:INAR1	involved_in	GO:0032728: positive regulation of interferon-beta production	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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