Zebrafish fkbp5 attenuates antiviral innate immunity by autophagic degradation of transcription factor irf7.

Activation of the type I interferon (IFN-I) signaling pathway is crucial for protecting host cells against viral infections. IFN-I production requires the transcription factors IFN regulatory factor 3 (IRF3) and IRF7, and its regulation must be finely tuned to both combat infection effectively and prevent excessive immunopathology. Here, we report that selective autophagy mediated by zebrafish FK506-binding protein 5 (Fkbp5), a PPIase (peptidyl-prolyl isomerase) promotes the degradation of Irf7 and Irf3, thereby inhibiting virus-induced type I IFN production. Quantitative real-time reverse-transcription polymerase chain reaction experiments indicate that zebrafish fkbp5 is induced by viral infection. Moreover, disrupting fkbp5 in AB-line zebrafish using CRISPR/Cas9 enhances survival rates and reduces viral messenger RNA levels compared with wild-type zebrafish. In cell culture, using promoter analysis and quantitative real-time reverse-transcription polymerase chain reaction, we found fkbp5 overexpression significantly attenuates cellular antiviral capacity and facilitates viral proliferation. Mechanistically, we found that fkbp5 inhibits Irf3/7-induced IFN activation, which depends on the binding of Fkbp5 to the Irf3 or IRF association domain of Irf7 via co-immunoprecipitation and Western blot assays. Furthermore, Fkbp5 induces the autophagic degradation of Irf3 and Irf7 independent of its PPIase activity. Blocking autophagy in vivo and in vitro restores the regulation of the RLR (RIG-I-like receptor) pathway by fkbp5. These findings reveal a critical role for zebrafish fkbp5 in suppressing the activation of Irf7 and Irf3 for IFN signaling and antiviral immune responses.