FK506-binding protein 5 (FKBP5, also known as FKBP51) interacts with kinases, such as CHUK (IKKα), IKBKB (IKKβ), and IKBKE (IKKε), promoting their kinase activity in response to various stimuli (Romano S et al., 2015; Kästle M et al., 2018;Hao W et al., 2020). This interaction is facilitated through FKBP51's scaffold and isomerase functions, which promote IKK complex assembly and catalytic activity (Romano S et al., 2015). Notably, FKBP51 silencing has been shown to significantly reduce NF-kappaB activation and pro-inflammatory cytokine production in vitro and in vivo (Kästle M et al., 2018; Gan YL et al., 2024). Bioinformatics analyses further confirm the regulatory function of FKBP5 in the NF-kappaB signaling pathway (Liu T et al., 2024).
Interaction between FKBP5 and interferon-induced protein 44 (IFI44) or IFI44-like (IFI44L) was found to inhibit phosphorylation of key signaling molecules IkBa and IRF3 by the IKK complex (CHUK:IKBKB:IKBKG) and IKBKE, respectively, suppressing induction of pro-inflammatory cytokine and type I IFN responses (DeDiego ML et al., 2019a, b). Here we show that the formation of the FKBP5:CHUK:IKBKB:IKBKG complex is negatively regulated by IFI44L,IFI44:FKBP5. However, the inhibition occurs because IFI44L or IFI44 sequesters FKBP5 thereby preventing its binding to the CHUK:IKBKB:IKBKG complex.
