IRF3 attenuates hypoxia signaling by retaining HIF-α in the cytoplasm

Interferon regulatory factor 3 (IRF3) functions as a key transcription factor in the innate antiviral immune response, which depends on its nuclear localization. However, its function in the cytoplasm during non-infection states remains largely unknown. In this study, we found that resting cytoplasmic IRF3 interacts with hypoxia-inducible factor (HIF)-1α and HIF-2α, two master regulators of hypoxia signaling. This interaction retains HIF-α in the cytoplasm under hypoxic conditions, preventing it from exerting its transcription factor function and attenuating hypoxia signaling. Disruption of IRF3 in both mice and zebrafish resulted in increased expression of hypoxia response genes and enhanced tolerance to hypoxia. These findings suggest that, in the absence of viral infection, cytoplasmic IRF3 modulates hypoxia signaling by retaining HIF-α in the cytoplasm under hypoxic conditions.