Zebrafish FKBP5 facilitates apoptosis and SVCV propagation by suppressing NF-κB signaling pathway

Abstract

FK506-binding protein 5 (FKBP5), encoded by FKBP5 gene, has been reported as a scaffolding protein in various mammalian pathways related to immunity, inflammation, apoptosis and autophagy. However, the role of FKBP5 in lower vertebrates remains unknown. In this study, we identified zebrafish FKBP5 (DrFKBP5), an ortholog of mammalian FKBP5, which shows high homology with its counterpart in Anabarilius grahami based on amino acid alignment and phylogenetic analysis. DrFKBP5 was found to express ubiquitously across all tested tissues. Its expression were significantly upregulated in eye, intestine, gill, skin, heart, liver and kidney following SVCV treatment. A similar expression pattern was also observed in EPC and ZFIN cells. DrFKBP5 decreased the promoter activitiy of NF-κB and IL-6 rather than IFN I. It also inhibited the expression of inflammatory factor genes such as IL-6, IL-1β and TNF-α. In molecular mechanism, we found that DrFKBP5 interacted with IKKβ (an activator of NF-κB pathway), but not with IKKα or IKKγ, suggesting that DrFKBP5 regulates NF-κB pathway by targeting IKKβ. Then, DrFKBP5 significantly reduced the phosphorylation of IKKβ. Furthermore, it inhibited SVCV-induced nuclear translocation, phosphorylation of p65 and promoted SVCV replication in ZFIN cells. Finally, DrFKBP5 activated the expression of apoptosis-related genes, including BAX, Bcl2, caspase-3 and induced apoptosis under SVCV treatment.