Upon viral infection, interferon regulatory factor 3 (IRF3) undergoes phosphorylation and activation. It then translocates to the nucleus where it dimerizes and functions as a key transcription factor that initiates the innate antiviral response. In the resting state, IRF3 is located in the cytosol and is inactivated. However, its function in the cytoplasm during non-infection states remains unclear.

In a study published in Cell Reports, a research group led by Prof. XIAO Wuhan from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences identified that IRF3 is a negative regulator of hypoxia signaling by retaining hypoxia-inducible factor α (HIF-α) in the cytoplasm.

Researchers first discovered that IRF3 negatively regulates the hypoxia signaling pathway. The suppressive role of IRF3 on hypoxia signaling depended on its localization in the cytosol. Knockout of IRF3 enhanced hypoxia response gene expression and potentiated cellular hypoxia adaptation.

Moreover, researchers revealed that under hypoxic conditions, cytoplasmic IRF3 interacted with HIF-1α and HIF-2α, two master regulators of hypoxia signaling. This interaction prevented HIF-1/2α from entering the nucleus and exerting its transcription factor function, thereby attenuating hypoxia signaling.

Using mice and zebrafish as in vivo models, researchers confirmed that disrupting irf3 increased hypoxia responsive gene expression and enhanced hypoxia tolerance.

This study reveals the role of IRF3 in non-infection states by modulating the hypoxia signaling pathway, and offers insight into crosstalk between two important ancient stress signaling pathways, the innate immunity pathway and the hypoxia pathway.

A working model for the role of IRF3 under hypoxic conditions or upon viral infection. (Image by IHB)