FAF1 downregulation by Toxoplasma gondii enables host IRF3 mobilization and promotes parasite growth

• Published in: Journal of cellular and molecular medicine 2021-10, Vol.25 (19), p.9460-9472
• Main Authors: Gao, Fei‐Fei, Quan, Juan‐Hua, Choi, In‐Wook, Lee, Yeon‐Jae, Jang, Seul‐Gi, Yuk, Jae‐Min, Lee, Young‐Ha, Cha, Guang‐Ho
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT; AKT protein; Antibodies; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; ARPE‐19 cells; Cell Line; Cells, Cultured; FAF1; Fluorescent Antibody Technique; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; Gene expression; Gene Expression Regulation; Host-Parasite Interactions - genetics; Humans; Infections; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; IRF3; Kinases; Laboratories; Membranes; Metabolism; Nuclear transport; Original; Parasites; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Reagents; Signal Transduction; Toxoplasma - physiology; Toxoplasma gondii; Toxoplasmosis - genetics; Toxoplasmosis - metabolism; Toxoplasmosis - parasitology; Transcription factors
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16889

Fas‐associated factor 1 (FAF1) has gained a reputation as a member of the FAS death‐inducing signalling complex. However, the role of FAF1 in the immunity response is not fully understood. Here, we report that, in the human retinal pigment epithelial (RPE) cell line ARPE‐19 cells, FAF1 expression level was downregulated by Toxoplasma gondii infection, and PI3K/AKT inhibitors reversed T. gondii‐induced FAF1 downregulation. In silico analysis for the FAF1 promoter sequence showed the presence of a FOXO response element (FRE), which is a conserved binding site for FOXO1 transcription factor. In accordance with the finding, FOXO1 overexpression potentiated, whereas FOXO1 depletion inhibited intracellular FAF1 expression level. We also found that FAF1 downregulation by T. gondii is correlated with enhanced IRF3 transcription activity. Inhibition of PI3K/AKT pathway with specific inhibitors had no effect on the level of T. gondii‐induced IRF3 phosphorylation but blocked IRF3 nuclear import and ISGs transcription. These results suggest that T. gondii can downregulate host FAF1 in PI3K/AKT/FOXO1‐dependent manner, and the event is essential for IRF3 nuclear translocation to active the transcription of ISGs and thereby T. gondii proliferation.