New Insight into FKBP12’s Involvement in Cry1Ac-Induced Toxicity to Helicoverpa armigera

FKBP12, the 12-kDa FK506-binding protein, plays a critical role in insect development and mammalian ABC transporter regulation. Our previous work showed that FK506 enhanced Cry1Ac toxicity in Helicoverpa armigera . We hypothesized that binding of FK506 to FKBP12 disrupted ABCC2 function, thereby influencing Cry1Ac toxicity. To test this, we examined FKBP12’s effect on Cry1Ac toxicity and its interaction with ABCC2. We found that both FKBP12 and ABCC2 were downregulated in Cry1Ac-exposed and resistant H. armigera . Silencing HaFKBP12 significantly decreased the susceptibility of Helicoverpa zea midgut cells to Cry1Ac, whereas overexpressing it in Sf9 cells increased the susceptibility. FKBP12 directly binds ABCC2 and modulates its transport activity. Importantly, HaFKBP12 overexpression enhances the HzABCC2 sensitivity to Cry1Ac. These findings show that FKBP12 regulates ABCC2 to influence Cry1Ac toxicity, expanding our understanding of Bt toxin mechanisms. Moreover, the interaction between FKBP12 and ABCC2 offers insights into overcoming ABC transporter-mediated pesticide resistance and identifying new insecticidal targets.