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.