Upon
infection, pathogen recognition leads to a rapidly activated gene expression program that induces antimicrobial effectors to clear the invader. We recently found that
Nup98 regulates the expression of a subset of rapidly activated
antiviral genes to restrict disparate
RNA virus infections in Drosophila by promoting
RNA polymerase occupancy at the promoters of these
antiviral genes. How
Nup98 specifically targets these loci was unclear; however, it is known that
Nup98 participates with
transcription factors to regulate developmental-gene activation. We reasoned that additional
transcription factors may facilitate the Nup98-dependent expression of
antiviral genes. In a genome-wide RNA interference (RNAi) screen, we identified a relatively understudied
forkhead transcription factor, FoxK, as active against Sindbis virus (SINV) in Drosophila. Here we find that FoxK is active against the panel of viruses that are restricted by
Nup98, including SINV and
vesicular stomatitis virus (VSV). Mechanistically, we show that FoxK coordinately regulates the Nup98-dependent expression of
antiviral genes. Depletion of FoxK significantly reduces Nup98-dependent induction of
antiviral genes and reduces the expression of a forkhead response element-containing
luciferase reporter. Together, these data show that FoxK-mediated activation of gene expression is
Nup98 dependent. We extended our studies to mammalian cells and found that the mammalian ortholog FOXK1 is
antiviral against two disparate RNA viruses, SINV and VSV, in human cells. Interestingly, FOXK1 also plays a role in the expression of
antiviral genes in mammals: depletion of FOXK1 attenuates virus-inducible
interferon-stimulated response element (ISRE) reporter expression. Overall, our results demonstrate a novel role for FOXK1 in regulating the expression of
antiviral genes, from insects to humans.
IMPORTANCE: Innate immunity is characterized by rapid gene expression programs, from insects to mammals. Furthermore, we find that
Nup98, known for its roles in the nuclear pore, plays a noncanonical role in binding the promoters and poising a subset of loci for rapid
antiviral gene induction. It was unclear how
Nup98 accesses these specific genes, and we here demonstrate that
Nup98 cooperates with the
transcription factor FoxK to regulate this gene expression program. Depletion of FoxK specifically reduces the induction of Nup98-dependent genes. Further, we find that the
antiviral function of FoxK is conserved, as the human ortholog FOXK1 is also
antiviral and regulates gene expression from virus-induced promoters. Although other
forkhead transcription factors have been implicated in immunity, a role for FoxK in
antiviral defense was previously unappreciated. Our findings reveal a conserved and novel role for FoxK in coordinating with
Nup98 to promote a robust and complex
antiviral transcriptional response.