MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling

•MEKK3 stimulate IRF7 upon cellular activation of the TLR7/9 signaling pathways to induce various type I IFNs.•The knockdown of MEKK3 in vivo substantially impairs type I IFN induction and increases susceptibility to HSV-1 infection in mice.•Overexpression of MEKK3 significantly activates IRF7 to trigger strong induction of type I IFNs.•IFNs’ induction is due to a MEKK3 and IRF7 interaction.•Endogenous MEKK3 can bind and phosphorylate IRF7 after TLR9 activation by its specific ligand CpG DNA.