Schizophrenia risk candidate protein ZNF804A interacts with STAT2 and influences interferon-mediated gene transcription in mammalian cells

Previously evidence was presented that the single-nucleotide polymorphism rs1344706 located in an intronic region of the ZNF804A gene is associated with reduced transcript levels in fetal brains. This genetic variation in the gene encoding the zinc-finger protein ZNF804A is associated with schizophrenia (SZ) and bipolar disorder. Currently, the molecular and cellular function of ZNF804A is unclear. Here, we generated a high-confidence protein-protein interaction (PPI) network for ZNF804A using a combination of yeast two-hybrid and bioluminescence-based PPI detection assays, directly linking 12 proteins to the disease-associated target protein. Among the top hits was the signal transducer and activator of transcription 2 (STAT2), an interferon-regulated transcription factor. Detailed mechanistic studies revealed that STAT2 binds to the unstructured N-terminus of ZNF804A. This interaction is mediated by multiple short amino acid motifs in ZNF804A but not by the conserved C2H2 zinc-finger domain, which is also located at the N-terminus. Interestingly, investigations in HEK293 cells demonstrated that ZNF804A and STAT2 both co-translocate from the cytoplasm into the nucleus upon interferon (IFN) treatment. Furthermore, a concentration-dependent effect of ZNF804A overproduction on STAT2-mediated gene expression was observed using a luciferase reporter, which is under the control of an IFN-stimulated response element (ISRE). Together these results indicate the formation of ZNF804A:STAT2 protein complex and its translocation from the cytoplasm into the nucleus upon IFN stimulation, suggesting that it may function as a signal transducer that activates IFN-mediated gene expression programs.