Abstract
Recent studies have documented the diverse role of host immunity in infection by the protozoan parasite, Toxoplasma gondii. However, the contribution of the β-catenin pathway in this process has not been explored. Here, we show that AKT-mediated phosphorylated β-catenin supports T. gondii multiplication which is arrested in the deficiency of its phosphorylation domain at S552 position. The β-catenin-TCF4 protein complex binds to the promoter region of IRF3 gene and initiates its transcription, which was also abrogated in β-catenin knockout cells. TBK-independent phosphorylation of STING(S366) and its adaptor molecule TICAM2 by phospho-AKT(T308S473) augmented downstream IRF3-dependent IDO1 transcription, which was also dependent on β-catenin. But, proteasomal degradation of IDO1 by its tyrosine phosphorylation (at Y115 and Y253) favoured parasite replication. In absence of IDO1, tryptophan was catabolized into melatonin, which supressed cellular reactive oxygen species (ROS) and boosted parasite growth. Conversely, when tyrosine phosphorylation was abolished by phosphosite mutations, IDO1 escaped its ubiquitin-mediated proteasomal degradation system (UPS) and the stable IDO1 prevented parasite replication by kynurenine synthesis. We propose that T. gondii selectively utilizes tryptophan to produce the antioxidant, melatonin, thus prolonging the survival of infected cells through functional AKT and β-catenin activity for better parasite replication. Stable IDO1 in the presence of IFN-γ catabolized tryptophan into kynurenine, promoting cell death by suppressing phospho-AKT and phospho-β-catenin levels, and circumvented parasite replication. Treatment of infected cells with kynurenine or its analogue, teriflunomide suppressed kinase activity of AKT, and phosphorylation of β-catenin triggering caspase-3 dependent apoptosis of infected cells to inhibit parasite growth. Our results demonstrate that β-catenin regulate phosphorylated STING-TICAM2-IRF3-IDO1 signalosome for a cell-intrinsic pro-parasitic role. We propose that the downstream IRF3-IDO1-reliant tryptophan catabolites and their analogues can act as effective immunotherapeutic molecules to control T. gondii replication by impairing the AKT and β-catenin axis.
Highlights
Toxoplasma gondii, an intracellular coccidium that has been coevolving with vertebrates over billions of years, commonly infects warm-blooded animals including humans[1]
These results documented that T. gondii infection upregulates both β-catenin and TCF, and we hypothesized that their heterodimeric complex is required for several downstream pathways
It is interesting to note that several IRF3-depedent interferon stimulated genes (ISGs) molecules supported parasite growth[10,38]
Summary
Toxoplasma gondii, an intracellular coccidium that has been coevolving with vertebrates over billions of years, commonly infects warm-blooded animals including humans[1]. Official journal of the Cell Death Differentiation Association. Majumdar et al Cell Death and Disease (2019)10:161 Page 2 of 19 161. T. gondii modulates a number of cell survival pathways to promote its replication and infection in host cells. In canonical Wnt-mediated signalling which is one of the major survival pathways, the serine-threonine protein kinase, AKT, phosphorylates β-catenin at Ser[552] phosphosite[2,3,4], as a result, cytosolic phospho-β-catenin accumulates and enters the nucleus to interact with T cell factor/lymphoid enhancer-binding factor (TCF/LEF). Family of transcription factors to promote transcription of several target genes[5,6,7]. Accumulating evidence has suggested that crosstalk between T. gondii infection and Wnt/β-catenin pathway regulates host gene expression[8,9].
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