Viral infection drives cell-intrinsic re-localization of the C. elegans immune-repressive STAT transcription factor STA-1

Abstract

Detection of viral infection leads to both cell-intrinsic and cell-extrinsic responses. In mammals, cell-intrinsic detection of viral infection leads to cell-extrinsic activation of STAT (Signal Transduction and Activators of Transcription) proteins, a family of transcription factors that promote anti-viral defense. In the nematode C. elegans, STA-1/STAT is a negative regulator of anti-viral defense, but it is not known if it acts cell-intrinsically or cell-extrinsically and whether it has functional domains conserved with mammalian STATs. Here we show that C. elegans STA-1 protein disappears from nuclei of cells infected with the natural viral pathogen, Orsay virus, but remains nuclear in uninfected cells, indicating a cell-intrinsic site of action. During viral infection, STA-1 forms cytoplasmic puncta that interact with the RNA viral sensor DRH-1, suggesting that DRH-1 helps restrain this immune-repressive factor. STA-1 overexpression causes increased susceptibility to viral infection, in a manner dependent on conserved residues important for DNA binding, nuclear localization and phosphorylation. Structural predictions indicate that STA-1 is most similar to STAT5 proteins in mammals, which have known immune-repressive roles. Our transcriptomic analysis demonstrates that C. elegans STA-1 regulates a general anti-pathogen program, including genes upregulated later during viral infection. Altogether, our findings provide insight into conserved and distinct features of STA-1 in C. elegans, indicating an ancient role for cell-intrinsic, immune-repressive STATs. Author SummaryAll living organisms must detect viral infections and mount a defense to survive. One major antiviral defense pathway in mammals is the interferon response, which involves sensing viral infection in one cell, and delivering an interferon message to neighboring cells. These neighboring cells then turn on anti-viral defense gene expression using proteins called STAT transcription factors. We study anti-viral defense in the roundworm C. elegans, and in this study show that viral infected cells themselves use a STAT protein called STA-1, with perhaps a lesser role for STA-1 in neighboring cells, in contrast to mammals. We also extend on previous findings that STA-1 turns off anti-viral gene expression, and we analyze regions in the protein to demonstrate that STA-1 is bona fide transcription factor with an immune-repressive role. Structural prediction analysis of STA-1 indicates it is most similar to STAT5 in mammals, suggesting an ancient role for this protein as an immune-repressive factor acting directly in virally infected cells.